Introduction

Biotechnology inventors have it easy. Powerful tools are now present to permit the exploration of life at its most fundamental level. From PCR to PC’s, molecular biologists have the tools to identify and analyze all the genetic information of a particular species. With this ocean of genetic opportunity, inventions can be made at a fast and furious pace.

Biotechnology patent professionals do not have it so easy. They work in an arena of limited judicial and administrative precedent. They must digest and make legal sense of the masses of scientific information that can be produced with breath-stealing speed. Moreover, they must justify to inventors and their corporate and university assignees the costs, uncertainties, and limitations the profession faces in seeking to broadly patent their pioneering research results.

Biodiversity itself appears to assure a steady stream of potentially patentable discoveries. Compounding the opportunities for patenting is the reality that genetic information differs markedly between species. Each time the DNA of a new strain of even a simple, single-cell organism is completed, hundreds to thousands of novel and nonobvious DNA sequences are discovered, foretelling the existence of an equal complement of novel and nonobvious proteins.

However novel and nonobvious it might be, new DNA and new proteins do not patent themselves. Crucial issues of patentability are manifest in attempting to effectively and exclusively claim the seemingly endless wealth of novel and non-obvious subject matter that flows from biodiversity. Among the many issues related to effective patenting of modern biotechnology inventions are the following three:

• If you have discovered a thousand proteins, related by source but not by structure, do you need to file a thousand patent applications to obtain effective patent coverage?
• If you have unraveled DNA coding all or part of a host of novel genes, what is the "practical utility" needed for a complete patent application?
• If you are the pioneer in discovering some new genetic milestone, how can the invention be claimed to provide some commercially meaningful protection — not just be limited to the new DNA sequence that is the actual and sole source of the discovery?

This paper takes a brief frolic into these issues for the biotechnology inventor from the vantage point of U.S. patent law and practice.

Disunity: Genes as "Independent and Distinct" Inventions, One from the Other

The U.S. Patent and Trademark Office uses two distinct standards for addressing the issue of whether or not claims should be restricted as a formal matter such that the filing of a divisional patent application will normally be needed to secure protection of all the potentially novel and non-obvious subject matter disclosed in an application for patent. For applications filed under the Patent Cooperation Treaty, the U.S. Patent and Trademark Office discharges its treaty obligations by applying the "unity of invention" standard under the PCT ¹.Moreover, the practice of the U.S. Patent and Trademark Office is to respect during national stage prosecution of an international (PCT) application, the determination of unity:

Any international application must relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (PCT Article 3(4)(iii) and 17(3)(a), PCT Rule 3.1, and 37 CFR 1.475). Observance of this requirement is checked by the International Searching Authority and may be relevant in the national (or regional) phase.

The decision in Caterpillar Tractor Company v. Commissioner of Patents and Trademarks , 231 U.S.P.Q. 590 (E.D. Va. 1986), held that the Patent and Trademark Office interpretation of 37 CFR 1.141(b)(2) as applied to unity of invention determinations in international applications was not in accordance with the Patent Cooperation Treaty and its implementing regulations. In the Caterpillar international application, the USPTO acting as an International Searching Authority, had held lack of unity of invention between a set of claims directed to a process for forming a sprocket and a set of claims drawn to an apparatus (die) for forging a sprocket. The court stated that it was an unreasonable interpretation to say that the expression "specifically designed" as found in former PCT Rule 13.2(ii) means that the process and apparatus have unity of invention if they can only be used with each other, as set forth in MPEP § 806.05(e).

Therefore, when the Office considers international applications as an International Searching Authority, as an International Preliminary Examining Authority, and during the national stage as a Designated or Elected Office under 35 U.S.C. 371, PCT Rule 13.1 and 13.2 will be followed when considering unity of invention of claims of different categories without regard to the practice in national applications filed under 35 U.S.C. 111. No change was made in restriction practice in United States national applications filed under 35 U.S.C. 111 outside the PCT.

The alternative to the PCT’s "unity of invention" rule is the domestic U.S. practice of looking at the possible "independent and distinct" nature of subject matter present in patent applications. The Manual of Patent Examining Procedure defines both these terms for U.S. patent examiners in section 802.01:

• "The term ‘independent’ (i.e., not dependent) means that there is no disclosed relationship between the two or more subjects disclosed, that is, they are unconnected in design, operation, or effect, for example: (1) species under a genus which species are not usable together as disclosed or (2) process and apparatus incapable of being used in practicing the process."
• "The term ‘distinct’ means that two or more subjects as disclosed are related, for example, as combination and part (subcombination) thereof, process and apparatus for its practice, process and product made, etc., but are capable of separate manufacture, use, or sale as claimed, AND ARE PATENTABLE (novel and unobvious) OVER EACH OTHER (though they may each be unpatentable because of the prior art). It will be noted that in this definition the term related is used as an alternative for dependent in referring to subjects other than independent subjects."

The grave difficulty for many biotechnology inventors is that under either of these two definitions, a single discovery can produce a hoard of disunified, independent and distinct inventions, potentially requiring the filing of a hoard of divisional patent applications to reassemble claims to the discovery as a whole. Given that patent applications have been filed encompassing hundreds to thousands — to perhaps tens of thousands — of gene sequences, who can afford filing a thousand applications costing nearly a thousand dollars each?

The U.S. Patent and Trademark Office has not been unsympathetic to the impracticability of filing divisional patent applications by the thousands. In 1996, Commissioner Lehman set out a policy under which the Office would maintain inventions together in the parent patent application:

Nucleotide sequences encoding different proteins are structurally distinct chemical compounds and are unrelated to one another. These sequences are thus deemed to normally constitute independent and distinct inventions within the meaning of 35 U.S.C. § 121. Absent evidence to the contrary, each such nucleotide sequence is presumed to represent an independent and distinct invention, subject to a restriction requirement pursuant to 35 U.S.C. § 121 and 37 C.F.R. §1.141 et seq. Nevertheless, to further aid the biotechnology industry in protecting its intellectual property without creating an undue burden on the Office, the Commissioner has decided sua sponte to partially waive the requirements of 37 C.F.R. §1.141 et seq. and permit a reasonable number of such nucleotide sequences to be claimed in a single application.

Accordingly, in most cases, up to ten (10) independent and distinct nucleotide sequences will be examined in a single application without restriction. It has been determined that normally ten sequences constitute a reasonable number for examination purposes. The PTO believes that allowing applicants to claim up to ten (10) independent and distinct nucleotide sequences in a single application will promote efficient, cost- effective examination of these types of applications. In addition to the specifically selected sequences, those sequences which are patentably indistinct from the selected sequences will also be examined. Furthermore, nucleotide sequences encoding the same protein are not considered to be independent and distinct inventions and will continue to be examined together.

In some exceptional cases, the complex nature of the claimed material, for example a protein amino acid sequence reciting three dimensional folds, may necessitate that the reasonable number of sequences to be selected be less than ten (10). In other cases, applicants may petition pursuant to 37 C.F.R. § 1.181 for examination of additional nucleotide sequences by providing evidence that the different nucleotide sequences do not cover independent and distinct inventions.

Commissioner’s Notice, October 17, 1996.

The practice as announced for national patent applications is further applied to international patent applications:

International applications filed under the Patent Cooperation Treaty (PCT) and national stage applications filed under 35 U.S.C. § 371 will be treated in a similar manner. Under 37 C.F.R. §1.475 and §1.499 et seq., when claims do not comply with the requirement of unity of invention, i.e., when the claimed subject matter does not involve "one or more of the same or corresponding special technical features," 37 C.F.R. §1.475(a), an additional fee is required to maintain the claims in the same application. 37 C.F.R. §1.476(b).

Commissioner’s Notice, October 17, 1996.

This practice, accordingly, avoids the need to pay excess search fees for applications in which the United States is the International Searching Authority ² The mathematical implications of the U.S. Patent and Trademark. Office’s practice for sequence-type claims is straightforward. U.S. applicants are ten times better off than they would have been had each sequence been a separate invention. However, they still face dozens to hundreds of potential divisional applications where the inventions include a broad array of new DNA sequences. Thus, the legal bill may fall from the millions of dollars to mere hundreds of thousands of dollars to file on all elements of an invention that is, for example, a fully sequenced bacterial genome.

Utility: All DNA Can Encode Polypeptides; All Polypeptides Can Serve As Useful Sources of Nutrients

Biotechnology holds great promise for mankind. Ergo, how could "practical utility" impede the ability of biotechnology inventors to obtain patents.

Biotechnology based research may lead to more powerful medicines, cures for the plagues that have followed mankind through the centuries, improved crops, more productive domesticated animal species, salvation for a natural environment ravaged by pollution, and even more conclusive molecular methods for tying murder suspects to their crimes. Despite this potential, a great many U.S. patent examiners have — over much of the past decade — imposed numerous rejections on biotech inventions for lack of utility!

Efforts to change the practice of patent examiners in imposing stringent utility requirements have focused on private sector efforts to have the Commissioner of Patents and Trademarks publish "Utility Guidelines." Ultimately, the Commissioner promulgated both "guidelines" and a sweeping legal analysis of the law on disclosures of utility for pharmaceutical- and biotechnology-related inventions. These Utility Guidelines effectively superseded the previous provisions of the Manual of Patent Examining Procedure, that, in § 608.01 (p), provided the only Patent and Trademark Office guidance for patent examiners with regard to utility rejections.

As indicated below, these new guidelines are largely positive for biotechnology inventors:

Proof of Safety.

The FDA has a clear Congressional mandate to prevent any drug from entering interstate commerce without first establishing that the drug is "safe" for its intended use. Safety goes to the heart of the FDA’s existence. In light of this, to what extent should the Patent and Trademark Office regard "safety" as bearing on utility and, thus, the ultimate question of patentability? The M.P.E.P. formerly resolved the "safety"/patentability issue for assertions of drug utility with the terse statement that:

Although absolute safety is not necessary to meet the utility requirement under this section, a drug which is not sufficiently safe under the conditions of use for which it is said to be effective will not satisfy the utility requirement (In re Hartop et al., 311 F.2d 249, 135 USPQ 419 (C.C.P.A. 1962); In re Anthony, 162 USPQ 594 (C.C.P.A. 1969); In re Watson, 186 USPQ 11 (C.C.P.A. 1975)). Proof of safety shall be required only in those cases where adequate reasons can be advanced by the examiner for believing that the drug is unsafe, and shall be accepted if it establishes a reasonable probability of safety.

Since "absolute safety" is either a non-existent or an unattainable goal for any drug, the M.P.E.P.’s requirement for "sufficient" safety provides some leeway for inventors. However, the issue of "sufficiency" creates a highly subjective standard of patentability: sufficient under what criteria? Moreover, the notion of being "sufficiently safe" inherently requires a cost-benefit assessment based on extensive clinical data. Finally, the issue of safety, if a serious consideration in the patent examination process, would implicate all the safety information available to the inventor as being possibly material to the patent examination process. Thus, the inventor would be obligated to disclose all of this information during examination.

The requirements for proof of safety pose even more complex problems for inventors. Safety is never decided in an abstract context for a pharmaceutical product, but rather in the context of conditions and indications for use. Safety is always relative; it is invariably true that drugs have side effects, even ultimately toxic side effects.

The new utility guidelines take a much more realistic view of what safety means in a patent context. The Patent and Trademark Office now takes the position:

The Examiner must confine his or her examination, for purposes of utility, to compliance with the statutory requirements of the patent law. Other agencies of the government have been assigned the responsibility of ensuring conformance to standards established by statute for the advertisement, use, sale or distribution of drugs.⁵³ Thus, while an applicant may on occasion need to provide evidence to show that an invention will work as claimed, it is improper for an Examiner to request evidence of safety in the treatment of humans, or regarding the degree of effectiveness.⁵⁴ [Footnotes omitted.]

Most interesting are the cases cited in support of the "no safety data" rule established under the guidelines. In footnote 54, the guidelines cite the very same cases that formerly were cited to support the contrary position, i.e., Hartop, Watson, and Anthony, as well as In re Sichert, 566 F.2d 1154, 196 USPQ 209 (1977), In re Krimmel, 292 F.2d 948, 130 USPQ 215 (C.C.P.A. 1961), and Ex parte Jovanovics, 211 USPQ 907 (Bd. Pat. App. & Inter. 1981).

From a former "safety" requirement that could have been so broadly read as to require complete FDA-style reporting, the Patent and Trademark Office appears to have now completely deferred the safety consideration to the FDA.

Human Testing Data

Nothing could be clearer than the Patent and Trademark Office’s current statement on the absence of the need for human clinical data. The new guidelines are adamant:

There is no decisional law that requires an applicant to provide data from human clinical trials to establish utility for an invention related to treatment of human disorders,⁵¹ even with respect to situations where no art-recognized animal models exist for the human disease encompassed by the claims.⁵² Examiners should not impose on applicants the unnecessary burden of providing evidence from human clinical trials. [Footnotes omitted.]

This recent revelation of the Office appears guided by a 30-year old decision of the Court of Customs and Patent Appeals, In re Isaacs, 347 F.2d 889, 146 USPQ 193 (1963). The guidelines extract the following quotation from Isaacs:

No authority has been cited and we have been able to find none which requires that in order to secure a patent, utility of a pharmacologically active substance must be proved by in vivo testing. The mere fact that the claimed invention may have possible utility in vivo does not warrant disregard of in vitro activity where the claims are not limited to in vivo use.

347 F.2d at 889, 146 USPQ at 195.

The former M.P.E.P. statements on human testing were, of course, constrained by the same body of law, but formulated the legal requirements somewhat less generously:

More particularly, if the utility relied on is directed solely to the treatment of humans, evidence of utility, if required, must generally be clinical evidence. (Ex parte Timmis, 123 USPQ 581 (Bd. App. 1959)) although animal tests may be adequate where the art would accept these as appropriately correlated with human utility (In re Hartop et al., 311 F.2d 249, 135 USPQ 419 (C.C.P.A. 1962); Ex parte Murphy, 134 USPQ 134 (Bd App. 1960)) or where animal tests are coupled with other evidence, including clinical evidence and a structural similarity to compounds marketed commercially for the same indicated uses, (In re Jolles, 628 F.2d 1322, 206 USPQ 885 (C.C.P.A. 1980)).

Inventors of human therapies — in biotechnology or any related pharmaceutical field of endeavor — have an obvious dilemma. Many of these inventors begin the arduous process of human clinical development with some basic pharmacological discovery. The discovery is typically made in an animal test system, sometimes only on isolated animal tissues. Given the practical need to publish promptly on basic discoveries, the timing of the patent application precedes any hope of human testing. Thus, the patent application will necessarily be devoid of direct proof of utility. Moreover, whether actual commercial utility — as opposed to "practical utility" — can ever be established depends on the rigorous FDA process. New drugs meeting the FDA standard are few and those few are estimated on average to require an investment of $500 million in research and development.

In light of these difficulties, it is fortunate that the Patent and Trademark Office appears to have adopted the position that credible science produces credible human therapy patents.

Credibility vs. Incredibility for an Asserted Utility.

The nub of the rejection for lack of utility has historically been grounded on the "incredibility" criterion. A patent examiner, on the basis of some evidence or reasoning, can assert that a disclosed utility is not to be believed. A person skilled in the art must regard the alleged utility as "incredible." In this case, rejections for either a lack of utility under 35 U.S.C. § 101 or a failure to enable use under 35 U.S.C. § 112 can be made — and were being routinely made — in biotechnology-related patent applications.

The gist of the pre-guideline rationale stated in the M.P.E.P. was the following:

If the asserted utility of a compound is believable on its face to persons skilled in the art in view of the contemporary knowledge in the art, then the burden is upon the examiner to give adequate support for rejections for lack of utility under this section [citations omitted.]. On the other hand, incredible statements [citations omitted] or statements deemed unlikely to be correct by one skilled in the art [citations omitted] in view of the contemporary knowledge in the art will require adequate proof on the part of applicants for patents.

The guidelines now make it reasonably clear that the "incredibility" standard does not apply to utilities within the mainstream of scientific endeavor. The standard appears in the guidelines as follows:

Cases decided by a Federal court in which a claimed invention was held to lack utility under § 101 because it was "inoperative" have been rare. Uniformly, in these cases the utility asserted by the applicant was "incredible in the light of knowledge of the art, or factually misleading"¹⁰ when initially considered by the Examiner. Examples include: an invention asserted to change the taste of food using a magnetic field,¹¹ a perpetual motion machine,¹² a method for increasing the energy output of fossil fuels upon combustion through exposure to a magnetic field,¹³ uncharacterized compositions for curing cancer¹⁴ and a method of restoring hair growth.¹⁵ In view of the rare nature of such cases, Examiners should not label an asserted utility "incredible" unless it is clearly appropriate to do so.

If the restatement of the law in the guidelines is faithfully followed by patent examiners, the "rare" rejection for lack of § 101 practical utility should become almost nonexistent in the industrial biotechnology arena. Since inventions of the industrial and academic biotechnology type are devoid of perpetual motion, rarely rely on magnetic or other mystical force fields or wholly uncharacterized (and, thus, mysterious) compositions, this form of rejection should all but disappear.

The Federal Circuit’s Utility Analysis in Brana

The Federal Circuit took the opportunity to review the Patent and Trademark Office’s utility guidelines in In re Brana.³ The court stated its view that "utility" issues for biologically useful subject matter were not issues of first impression:

At issue in this case is an important question of the legal constraints on patent office examination practice and policy. The question is, with regard to pharmaceutical inventions, what must the applicant prove regarding the practical utility or usefulness of the invention for which patent protection is being sought. It is not a new issue; it is one which we would have thought had been settled by case law years ago [footnote omitted.] We note the Commissioner has recently addressed this question in his Examiner Guidelines for Biotech Applications, see 60 Fed. Reg. 97 (1995); 49 Pat. Trademark & Copyright J. (BNA) No. 1210, at 245 (Jan. 5, 1995).

34 U.S.P.Q.2d 1439.

In Brana, the court reaffirmed the basic principle, set forth originally in Nelson v. Bowler⁴, that useful pharmacology represents practical usefulness and, therefore, disclosure of pharmacology is sufficient to meet the requirement for utility under 35 U.S.C. § 101. In Brana, disclosure of anti-tumor activity ("a better action and a better action spectrum as anti-tumor substances") was considered sufficient, particularly since the patent specification cited comparable compounds in the prior art that had been tested in two lymphocytic tumor models.

The Patent and Trademark Office argued that the failure of the application to "disclose a specific disease" rendered its claims unpatentable. The Federal Circuit rejected this argument, finding that the model system was enough for persons skilled in the art to infer specific therapeutic application:

Since one of the tested [prior art] compounds . . . was found to be highly effective against these two lymphocytic leukemia tumor models, applicants’ favorable comparison implicitly asserts that their claimed compounds are highly effective (i.e., useful) against lymphocytic leukemia.

Having lost on the question of specificity of the utility allegation, the Patent and Trademark Office’s second argument, that the inventor’s evidence of utility was "inadequate to convince one of ordinary skill in the art that the claimed compounds were useful as antitumor agents," was likewise rejected. The court responded to this assertion by reversing the playing field. It held that the examiner’s evidence that the claimed subject matter was not useful was inadequate to shift the burden to the inventor to demonstrate utility. The court held that the evidence relied upon by the Patent and Trademark Office — references discussing the correlation between tests in laboratory animals and effects in humans — could shift the burden of proof "only if applicants must prove the ultimate value in humans of their asserted utility."

Further, the court rejected the notion of inherently "incredible utility" as applying here:

The purpose of treating cancer with chemical compounds does not suggest an inherently unbelievable undertaking or involve implausible scientific principles [citations omitted.] Modern science has previously identified numerous successful chemotherapeutic agents. . . .

. . .

We do not rest our decision there, however. Even if one skilled in the art would have reasonably questioned the asserted utility, i.e., even if the PTO met its initial burden thereby shifting the burden to applicants to offer rebuttal evidence, applicants proffered sufficient evidence to convince one of skill in the art of the asserted utility. In particular . . . test results showing several compounds . . . exhibited significant activity against the L1210 standard tumor model in vivo.

34 U.S.P.Q.2d at 1441-2.

The Patent and Trademark Office suggested that the above standard animal model was not predictive of effects in humans, but the court totally rejected the notion that effects in humans were needed to establish that novel compounds were useful. The court again reiterated the appropriateness of useful pharmacology, and useful pharmacology alone, to establish practical utility:

Our court’s predecessor has determined that proof of an alleged pharmacological property for a compound by statistically significant tests with standard experimental animals is sufficient to establish utility. [Citations omitted.] In concluding that similar in vivo tests were adequate proof of utility the court in In re Krimmel stated:

We hold as we do because it is our firm conviction that one who has taught the public that a compound exhibits some desirable pharmacological property in a standard experimental animal has made a significant and useful contribution to the art, even though it may eventually appear that the compound is without value in the treatment of humans.

34 U.S.P.Q.2d at 1442.

The court also noted the distinction between FDA and PTO functions: "The stage at which an invention in this field becomes useful is well before it is ready to be administered to humans." In effect, the court was "endorsing" the broad outlines of the Commissioner’s utility guidelines by simply reiterating its longstanding precedents.

Post-Brana Guidance from PTO Officials: Utility for Bits & Pieces of Genes

Recently, John Doll, Director, Biotechnology Examination, Technology Center 1600, U.S. Patent and Trademark Office, waded into the most controversial area of gene patenting: rules regarding "expressed sequence tags" — small pieces of DNA encoding a complete gene and "single nucleotide polymorphism" — the single DNA base differences characterizing each individual member of a species ⁵.

Although some SNPs and ESTs may not directly identify genes, they may still be extremely useful and thus satisfy the utility requirement. SNPs and ESTs may have specific utilities that are separate and distinct from the genes to which they correspond. For example, SNPs can be used to trace ancestry or parentage. ESTs can be used for chromosome identification and gene mapping. Both can be used to identify genes that contribute to predisposition to disease.

Claims to DNA elements useful for forensic identification, the identification of tissue type or origin, chromosome mapping, chromosome identification, or tagging of a gene of known and useful function must fulfill the enablement requirement. For any invention, enablement is satisfied when, by reading the patent application, an individual who has skill in the technology would have been able to make and use the invention as intended without undue experimentation.

In fact, it is common for the patentability of DNA elements to hinge on whether sufficient information has been given to enable at least one credible or specific utility. Examples of potentially non-enabled utilities for a DNA sequence fragment include its use to locate disease-associated genes when the disease has no known genetic origin; as an antisense reagent when the corresponding protein to be suppressed is unknown; as a triplex probe to inhibit expression of a protein when the protein and its function are unknown; and to locate and identify genes of unknown utility.

The Doll optimism is far from a universal one, however. The last quoted paragraph above was the only view that the U.S. Patent and Trademark Office took when initially confronted with EST claims in the now-infamous "Venter EST applications." ⁶. The Venter EST application took great pains to identify "utilities" for the gene pieces obtained by randomly collecting and reporting DNA sequences found by "reverse transcribing" RNA found in human cells that was in the process of producing protein products encoded by the RNA. These utilities included:

• Probes to isolate coding sequences and complete genes, which may then be mapped to chromosomal locations.
• Chromosome markers.
• Isolation of complete genes through use of the EST probes.
• Expression of complete genesin recombinant host cells to obtain their protein products.
• Diagnostic probes, to detect the presence of a specific mRNA in a particular cell type, or in genetic linkage analysis, or to locate gene regions associated with genetic disease.
• Regulators of gene expression through triple helix formation or antisense methods.
• Individual identification for forensic and other purposes.
• Reagents to identify tissue specimens by organ type or by species.

The U.S. Patent and Trademark Office had no difficulty rejecting Venter’s ‘195 EST application for lack of utility (Office Action dated August 20, 1992):

The mere mention of general possible uses is not sufficient to establish a definite utility because the instant application does not disclose a patentable utility for the oligonucleotides or other nucleotides of the claimed inventions in their currently available form. Given what is disclosed in the instant application, it would be necessary for one to do further work in order to establish a utility for many of the nucleotides embraced by the claims. The instant application does not teach one of skill in the art the significance of any putative result of any of the tests or processes alluded to in the application. Although the oligonucleotides embraced by the claims may be hybridized to a variety of different preparations of other nucleic acids, one of skill in the art has no clue as to the significance of any results of such hybridization because the instant application fails to provide any basis for the interpretation of any putative results. Thus, given the invention in its currently available form, others would be compelled to experiment, interpret results, and invent a patentable utility for the claimed nucleotides.

The NIH sought a legal opinion ⁷ from leading patent law scholars on the utility issues presented by the examiner’s rejection. These scholars focused on the lack of specificity that Director Doll mentioned in his last paragraph:

In sum, although the utility issues raised by these patent applications have no clear answers, in light of recent caselaw it is not surprising that the PTO rejected the claims of the ‘195 application for lack of utility, nor would we be surprised to see the Federal Circuit affirm the rejection on this ground. The primary reasons for this reaction are: (1) many of the asserted utilities involve use for vaguely identified diagnostic or therapeutic purposes, with no indication of the particular diagnostic or therapeutic purposes for which any particular sequence or group of sequences might be used; (2) most of the sequences may not be put to the asserted uses without further experimentation which appears to go beyond routine experimentation, and the outcome of which is uncertain; and (3) the utilities that appear least problematic on enablement and operability grounds--use of the sequences as probes for finding full-length cDNAs or as chromosome markers--are most vulnerable to challenge on the ground that they are merely of interest to researchers and don’t yet amount to practical utility in currently available form.

23 AIPLA Q. J. 20.

With the liberalization apparent in the U.S. Patent and Trademark Office utility guidelines and the ambiguous attitude of Director Doll, it is now possible that the U.S. Patent and Trademark Office will be issuing patents that lack what the courts will eventually see as some "practical utility in currently available form."

Scope of Protection: Threading Patent Claims Through the Eye of the "Written Description"/Enablement" Needles of Patentability

The Underlying Problem Confronting Biotechnology Inventors: Function Dominates Form.

The U.S. Patent and Trademark Office has, however, granted a number of patents on biotechnology inventions, only to have these patents invalidated at the Court of Appeals for the Federal Circuit. Knowing what broad claims are unpatentably broad does not necessarily, however, provide guidance as to what commercially meaningful claims might meet the requirements for patentability.

Biotechnology inventors have an arsenal of distinct, but highly suspect armaments in their battles with patent examiners to broaden patent claims. One is to simply mandate that any related compounds that are bioactive are encompassed by the claims. Limitations of this type often appear as, "having in vivo biological activity against disease X." Since the patent laws presumably prevent the patenting of inert materials, limiting a patent claim to any material with any biological activity at all is, in reality, a non-limitation limitation. While this absurdity can be avoided by limiting the claims to compounds with appreciable activity, e.g., "having in vivo biological activity against disease X sufficient for commercial use as a medicine," such a limitation doesn’t avoid the central problem: a person skilled in the art is left to make and test endless compounds — in effect forcing the skilled person to make the very invention, the commercially useful drugs — that the inventor purported to have disclosed as justification for getting the claim in the first place.

Biotechnology, it seems, inherently lulls inventors into defining what they have invented in terms of what it does rather than what it is. If a potential protein drug is discovered through genetic engineering, a person skilled in the art can readily assume that numerous derivatives and analogues may share the same or a similar biological function. The original discoverer may synthesize a few of these analogues, demonstrate appreciable biological effects, and — understandably — attempt to lay claim to all the rest of the field that has been opened. As an example:

A protein, except as existing or occurring in nature, comprising:
(A) all or part of the amino acid sequence set forth in SEQ. ID. NOS. 1, 2 or 3;
(B) an amino acid sequence at least 50% homologous with an amino acid sequence defined in (A),
said protein having the in vivo biological property of stimulating the production of enzyme Y.

The inherent difficulty with a claim of the above scope under U.S. patent law lies both in the arena of a "written description" and the enablement. First, the genus — except for the biology limitation — is not merely large, but decidedly infinite. Once all the carbon atoms now existing in the universe have been used in the synthesis of only a relatively few of the various amino acid sequences contemplated by (A), there will be no matter left in the universe to finish making the vast remainder of (A), much less any of (B), much less proceed with the in vivo biological testing needed for (C). Further, although the preamble of the claim purports to limit the claim to non-naturally occurring proteins (avoiding a claim that reads on products of nature), the novelty of the claim rests on the possibly tenuous assumption that no known protein has the biological property of stimulating the production of enzyme Y. If such exists, the claim likely lacks novelty since (A) and (B) together potentially read on every protein under the sun. ⁸

Effectively, therefore, the above claim can be recast in simple, non-patent terms, as follows:

All the novel proteins (except for the naturally-occurring forms) that stimulate enzyme Y in vivo that have at least some substantial structural relationship to one of the three proteins actually described in the patent specification.

The Federal Circuit and one of its predecessor courts, the Court of Customs and Patent Appeals, have spent decades developing the basis on which claims, such as the above, can run afoul of the requirements for patentability. Judge Rich, in a 1963 dissent⁹, summarized a number of bases for invalidating such a claim:

The usual reasons for objection to functional language in claims are these:

1. The claim covers everything which would produce a stated result or effect. (Example: a "single-means" claim.)

2. The functional language gives the claim a scope such that it reads on the prior art. . . .

3. The claim is vague--the public cannot tell what would infringe it; it does not clearly define.

4. The scope of the claim is unjustifiably broad--it covers too much more than was actually invented and disclosed by the applicant.

137 U.S.P.Q. at 163.

Two of the four "reasons" set forth above are based on 35 U.S.C. § 112, first paragraph: the last of the four "reasons" is now recognized under the "written description" rubric, the first is now properly countenanced as an "enablement" defect. The third "reason" relates to potential indefiniteness under 35 U.S.C. § 112, second paragraph¹⁰. As recast, the above claim to the set of proteins stimulating enzyme Y is clearly a "single means claim" ¹¹ and clearly lacks enablement, if not definiteness.

However, Federal Circuit precedent has now clarified that the fourth reason set forth by Judge Rich — permitting the claim to cover much more than was actually invented — must be considered in terms of the "written description" requirement. Simply setting forth the objective of the inventive activity ("proteins that stimulate enzyme Y in vivo"), but not demonstrating possession of the corresponding things (i.e., chemical compounds or chemical structures demonstrating achievement of that objective), can only mean that the invention has neither been completely conceived nor otherwise possessed by the inventor. Possessing the objective for the invention is not possession of the invention itself.

The salient decision of the Federal Circuit in this regard is Fiers v. Revel¹². The Federal Circuit was asked to decide which of three rival foreign inventor groups had made an invention first (which, under then existing U.S. law, left the foreign inventors relying strictly on the filing dates of their patent applications). The common invention in issue was defined in terms of a simple claim (the "count" in patent interference terminology). This count effectively set forth the objective of the research:

A DNA which consists essentially of a DNA which codes for a human fibroblast interferon-beta polypeptide.

The Board of Patent Appeals and Interferences in the U.S. Patent and Trademark Office, concluded that evidence of a completed invention must be found in the patent application:

The Board . . . determined that Fiers’ disclosure of a method for isolating the DNA of the count, along with expert testimony that his method would have enabled one of ordinary skill in the art to produce that DNA, did not establish conception, since Τsuccess was not assured or certain until the [β-IF] gene was in fact isolated and its sequence known.’ The Board relied on our opinion in Amgen Inc. v. Chugai Pharmaceutical Co., in which we addressed the requirements necessary to establish conception of a purified DNA sequence coding for a specific protein. Accordingly, the Board held that Fiers was entitled only to the benefit of his April 3, 1980 British application date because only that application disclosed the complete nucleotide sequence of the DNA coding for β-IF. That date was subsequent to Sugano’'s March 1980 Japanese priority date. [Emphasis supplied.]

The Federal Circuit then went on to deny a second inventor the right to rely on a prior-filed patent application, even though again, it described the contested claim (count) and the manner by which it could be implemented in practice:

An adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself. [The second inventor’s] specification does not do that. [That] application does not even demonstrate that the disclosed method actually leads to the DNA, and thus that he had possession of the invention, since it only discloses a clone that might be used to obtain mRNA coding for β-IF. A bare reference to a DNA with a statement that it can be obtained by reverse transcription is not a description; it does not indicate that [the second inventor] was in possession of the DNA. [His] argument that correspondence between the language of the count and language in the specification is sufficient to satisfy the written description requirement is unpersuasive when none of that language particularly describes the DNA.

Thus, where the claim effectively reads on the inventor’s research objective, but the underlying patent specification does not describe a commensurate accomplishment of that objective, i.e., through the structures of the products encompassed by the claims, the invention has neither been conceived nor described. (There is under U.S. patent law the ability to avoid completely both the enablement and written description issues with the "all the novel proteins that stimulate enzyme Y" claim, provided a Hyatt-type "single means" format is avoided. If this can be done, the claim — although functional in a "means-plus-function" sense — is not objectionable under 35 U.S.C. § 112 ¹³ and, more importantly, provides a reasonable claim breadth ¹⁴ and the possibility to extend protection to corresponding products.¹⁵

Over the years, a number of techniques have been devised to claim the knowable, but as yet unaccomplished parameters of the invention. A few of the strategies that have been tried in the United States are set forth below.

Sufficient for Bioactivity.

The prototype of the "sufficient-for-bioactivity" claim was the Amgen claim in its erythropoietin patent (U.S. Patent 4,703,008, Lin):

7. A purified and isolated DNA sequence consisting essentially of a DNA sequence encoding a polypeptide having an amino acid sequence sufficiently duplicative of that of erythropoietin to allow possession of the biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells, and to increase hemoglobin synthesis or iron uptake.

As attractive as such a claim is to an inventor, it was unappealing to the Federal Circuit, and this claim was invalidated based on an insufficient support in working examples (or other description) of sufficiently duplicative sequences.

Hybridization.

Many inventors have attempted to obtain broad claims by describing as part of the invention DNA's that hybridize to an isolated clone: Amgen’s ‘008 erythropoietin patent contained such a claim:

1. A purified and isolated DNA sequence encoding erythropoietin, said DNA sequence selected from the group consisting of:
(a) the DNA sequences set out in FIGS. 5 and 6 or their complementary strands; and
(b) DNA sequences which hybridize under stringent conditions to the DNA sequences defined in (a).

Amgen patent attorneys were apparently building on the earlier claims draftsmanship in U.S. Patent 4,530,901, Lin (July 23, 1985), in which the hybridization claim read:

A recombinant DNA molecule consisting of segments of DNA. . . selected from the group consisting of:
(a) the DNA inserts of [named clones],
(b) DNA sequences which hybridize to any of the foregoing DNA inserts and which code on expression for a polypeptide of the IFN-α type, and
(c) DNA sequences which code on expression for a polypeptide of the IFN-α type coded for on expression of any of the foregoing DNA sequences and inserts . . . .

The IFN-α inventor creatively claimed (a) what he made, (b) whatever hybridizes to what he made and retains the characteristic biological activity, and (c) whatever is degenerate (in terms of the genetic code) with either of the above. The claims require stringent conditions while the IFN-α claims do not. This points to one of the difficulties with this approach: hybridization is not an unambiguous result. A second difficulty, of course, arises out of the very degeneracy of the genetic code. It is possible for a DNA encoding a totally unrelated polypeptide to "hybridize" under some conditions with one of the degeneracies here, yielding the prospect that these drafted claims could read on so many future unrelated inventions that accidentally share a pharmacological action as to fail to "particularly point out" the actual invention.

Significant Homology.

Some inventors have defined the knowable embodiments of a recombinant DNA invention by expanding claims to DNAs with "substantial" homology:

1. An isolated DNA molecular having a nucleotide sequence encoding a bovine adrenotropic hormone receptor wherein the DNA sequence is substantially homologous to the sequence in FIGS. 1A-1C (SEQ ID NO:3).

U.S. Patent 5,280,112, Jan. 18, 1994, Cone, et al.

Other inventors have injected breadth by devising a percentage of homology. As is apparent from the examples below, inventors expressing percentages have reached no consensus as to the proper quota (and, possibly, no rationale based on the prior art, scope of exemplication, or other non-arbitrary basis for establishing a quota):

(1) Forty Percent:

4. A vector comprising DNA encoding an insulin receptor or a fragment thereof encoding a biologically active insulin receptor polypeptide.
. . .
8. The vector of claim 4 wherein the DNA encodes a predetermined, site-specific mutant insulin receptor which is greater than about 40 percent homologous with the insulin receptor of FIG. 1b and which exhibits a biological activity in common with the insulin receptor of FIG. 1b.

U.S. Patent 4,761,371, Aug. 2, 1988, Bell, et al.

(2) Fifty Percent:

2. The DNA segment of claim 1, wherein said DNA segment comprises a segment selected from the group consisting of (a) a segment encoding amino acids 137 to 193 of SEQ ID NO: 2 and FIG. 13; (b) a segment encoding amino acids 159 to 215 of SEQ ID NO: 4 and FIG. 8; and (c) a segment encoding an amino acid sequence having at least 50% homology with the amino acid sequence of (a) or (b).

U.S. Patent 5,260,208, Nov. 9, 1993, Petre, et al.

(3) Seventy-Five Percent:

1. Isolated DNA encoding a vitamin K dependent carboxylase selected from the group consisting of: (a) isolated DNA selected from the group consisting of DNA which encodes bovine 94,000 dalton vitamin K dependent carboxylase and comprises the sequence . . . [listed]; (b) isolated DNA which hybridizes to the complementary strand of isolated DNA of (a) above under stringent conditions represented by a wash stringency of 0.3M NaCl, 0.03M sodium citrate, and 0.1% SDS at 70^o C. and which encodes a vitamin K dependent carboxylase at least 75% homologous to isolated DNA of (a) above; and (c) isolated DNA differing from the isolated DNAs of (a) and (b) above in nucleotide sequence due to the degeneracy of the genetic code, and which encodes a vitamin K dependent carboxylase.

U.S. Patent 5,268,275, Dec. 7, 1993, Stafford, et al.

(4) Ninety Percent:

1. A recombinant DNA molecule comprising a T-DNA 780 gene transcription activating element which comprises a nucleotide sequence as in Table 1, from about nucleotide - 427 to about nucleotide - 348 or a functionally equivalent nucleotide sequence with at least about 90% homology thereto and which further comprises a nucleotide sequence from about nucleotide - 290 to about nucleotide - 271 or a functionally equivalent nucleotide sequence, with at least about 90% homology thereto, and a plant-expressible gene comprising a TATA region wherein said gene is not the 780 gene and wherein said gene is expressed at an enhanced level under the regulatory control of said transcription activating element.

U.S. Patent 5,196,329, Mar. 23, 1993, Gurley, et al.

While this mathematical approach is more definite than a mere requirement for "substantiality," it suffers from the potential defect of being merely arbitrary. It could be viewed by a court as particularly pointing out or distinctly describing what the inventor believes that he or she can get away with, rather than demonstrating possession of something that was actually invented. The Amgen court, and even the Fiers v. Sugano court, might look to the patent specification for the experimental justification for the recited percentage, declining to validate a patent to an arbitrary guess.

"Written Description" Guidelines to the Rescue?

The U.S. Patent and Trademark Office has set forth draft guidelines ¹⁶ to assist both patent examiners and patent practitioners to wind their way through the thicket of caselaw that now defines at least in part the parameters for describing an invention being claimed. These guidelines were most proximately the result of the Federal Circuits Lilly decision.¹⁷ The issues in these guidelines were the subject of a pre-announcement commentary by Director Doll, speaking on behalf of the U.S. Patent and Trademark Office:

An area of patent law that is still developing relates to the kind of information that must be included in the patent application of a biotechnology-related invention in order to sufficiently identify and distinguish its characteristics from other subject matter (in other words, satisfaction of the written description requirement). In the case of the Regents of the University of California v. Eli Lilly, the court held that in order to claim a specific DNA sequence, such as the human DNA encoding insulin, more is required than a mere statement that it is part of the invention, plus a fragment of the claimed nucleic acid, plus a reference to a potential method of isolating the entire sequence. As a result of the Lilly case and several earlier cases, the USPTO is preparing interim examination guidelines for determining compliance with the written description requirement that should be made available for public comment within the next 3 months

There has been considerable debate and discussion over how the issuance of a patent on DNA fragments of a gene will affect the patenting of full-length genes. The USPTO views this situation as analogous to having a patent on a picture tube. The picture tube patent does not preclude someone else from obtaining a patent on a television set. However, the holder of the picture tube patent could sue the television set makers for patent infringement if they use the patented picture tube without obtaining a license.

In a second example, a patent might be granted for compound X, which is disclosed to have a specific use (such as a headache remedy). If other investigators find that X has a new and unexpected use, perhaps in combination with compound Y, for treatment of heart arrhythmias, they may have to obtain a license from the individual who first patented compound X in order to sell XY.

In summary, once a product is patented, that patent extends to any use, even those that have not been disclosed in the patent. A future nonobvious method of using that product may be patentable, but the first patent would have been dominant.

The Doll comments are curious in several respects. First, the "picture tube" has only utility if it can display a picture. Aimlessly shooting electrons at a phosphor to make it glow in the dark is the prior art; the television was the invention that gave meaning to the picture tube and the invention of the television is presumably the predicate discovery that would have permitted the picture tube itself to be patented.

Second, the analogy between the patenting of a bona fide product, compound X, and the inferential discovery of the putative partial structure of a still unknown product, is akin to finding an auburn hair at the murder scene and then claiming the reward when the murderer turns out to be a red-bearded madman. When there are many detectives at the scene of the crime, there are many potential reward claimants. Is it possible that a host of EST inventors might lay a rightful claim to a therapeutic protein product? Consider where the first claimant finds 30 DNA base pairs and claims the proteins made from the DNA comprising the 30 base pairs. The next claimant makes the very same claim with the first 40 base pairs, followed by claimants with 50, 60, 70 and 80. When the later discovery is made of the isolated and purified protein and its useful physiological property, is the ultimate inventor to share the rewards with six clue finders? Director Doll not only seems to think so, but views the EST patentees as the "primary patent holder":

A patent is granted to a large fragment of DNA, within which exists a gene of great medical interest, even though the location of the open reading frame with the fragment has not been determined. The person who actually discovers and isolates the gene may also be able to receive a patent. Alternatively, many patented DNA fragments such as ESTs or SNPs may be isolated that turn out to be part of the same gene. In both cases, the second patent holder may have to obtain licenses from or pay fees to the primary patent holder but is not prevented from obtaining the second patent.

The fallacy with the Doll compound X analogy is that the discovery of compound X is the discovery of the complete structure — or other complete and distinctive characterizing information — for compound X. The discovery of an EST sequence may be the discovery of the EST compound itself, but it is not legally or logically the discovery of every compound that merely contains that sequence.

The Lilly decision reflects an analogous concern over breadth. The University of California inventors were allegedly the first to discover a mammalian proinsulin DNA sequence, namely the cloning of rat proinsulin cDNA. The patent issued attempted to claim every mammalian proinsulin cDNA. This represented a group of specific compounds of unknown structure that would have produced a patent broad enough to cover, in particular, the as yet undiscovered human proinsulin cDNA compound. Hence, it appears impossible to reconcile the analogy offered by Director Doll on behalf of the USPTO ¹⁸and the clear guidance of the Federal Circuit.

The actual "written description" draft guidelines are no less problematic. Consider, for example, the opening salvo of argumentation:

A gene comprising SEQ ID NO: 1"; "A mRNA comprising SEQ ID NO: 1"; and "A cDNA comprising SEQ ID NO: 1" implicitly recite specific structures such as promoters, enhancers, coding regions, and other regulatory elements in the preamble which must be sufficiently described in the specification so as to show the applicant was in possession of the claimed inventions.

In contrast, use of less specific, generic preamble language, such as "composition," "nucleic acid," "DNA," and "RNA," does not typically present a written description problem. These terms are sufficiently general that one skilled in the art can readily envision a sufficient number of members of the claimed genus to provide written description support for the genus.

The guidelines — taken at face value — suggest that you can solve a written description defect by simply making the invention more generic, i.e., substantially broader in scope. While some circumstances may fit this general proposition, it would necessarily seem to be the exception and not a rule.

There are other strange anomalies in the guidelines. A further example is given for monoclonal antibodies:

[C]onsider the following claim to a genus:

A monoclonal antibody which specifically binds to the novel cancer associated TAG-31 antigen but which does not substantially bind normal adult human tissues, wherein said monoclonal antibody has a binding affinity of greater than 3 times 109 M-1 for TAG-31.

Considering the claim as a whole, it is drawn to a genus of monoclonal antibodies. Although the specification does not disclose the complete structure of a representative number of species to support the claimed genus of antibodies, it does disclose multiple monoclonal antibodies which have the isotype claimed as well as the binding specificity and binding affinity characteristics recited in the claims. In this well-developed art, additional identifying characteristics for a substantial portion of the genus are well-known (e.g., number of chains, disulfide bonds, constant and variable regions, etc.). Thus, applicant’s disclosure combined with what was known in the art are sufficient to describe the claimed genus of monoclonal antibodies in such full, clear, concise and exact terms to show applicant was in possession of the claimed antibodies.

What the U.S. Patent and Trademark Office guidelines suggest is a "well-developed art," is in fact an empirical and unpredictable art in terms of having structure-activity relationships. Further the "additionally identifying characteristics for a substantial portion of the genus" that are well known, are merely the general structural features common to every antibody produced in every mammalian cell type. Moreover, the claim reads on every antibody with an affinity "greater than 3 times" a benchmark reference. Such an open-ended scale clearly preempts future work in a manner that the courts have condemned in the past. See In re Fisher, 166 U.S.P.Q. 18, 427 F.2d 833 (C.C.P.A. 1970), where the Federal Circuit’s predecessor court sustained a rejection to a claim containing a minimum potency limitation: ¹⁹

The issue thus presented is whether an inventor who is the first to achieve a potency of greater than 1.0 for certain types of compositions, which potency was long desired because of its beneficial effect on humans, should be allowed to dominate all such compositions having potencies greater than 1.0, including future compositions having potencies far in excess of those obtainable from his teachings plus ordinary skill.

It is apparent that such an inventor should be allowed to dominate the future patentable inventions of others where those inventions were based in some way on his teachings. Such improvements, while unobvious from his teachings, are still within his contribution, since the improvement was made possible by his work. It is equally apparent, however, that he must not be permitted to achieve this dominance by claims which are insufficiently supported and hence not in compliance with the first paragraph of 35 U.S.C. 112. That paragraph requires that the scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art. In cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved. In the present case we must conclude, on the record before us, that appellant has not enabled the preparation of ACTHs having potencies much greater than 2.3, and the claim recitations of potency of "at least 1" render the claims insufficiently supported under the first paragraph of 35 U.S.C. 112. [Emphasis supplied.]

166 U.S.P.Q. at p. 23-24.

It remains to be seen how the "written description" issue will ultimately be resolved and to what extent it will limit the scope of valid patent claims in the biotechnology arena. However, given the public statements of Director Doll and the proposed guidelines of the U.S. Patent and Trademark Office, it appears that the Office will only serve as a limited impediment to getting broad biotechnology patent claims, leaving it to the courts — not the Office — to eventually trim the excess.

Conclusions

The biotechnology inventor appears to have overcome the Dark Ages of patent prosecution in the United States. The patent examiners who so forcefully restated meritless rejections for lack of utility have given way to a new breed of patent examiner who not only finds useful inventions useful, but appears prepared to step up to if not over the line on what is a practical utility in a presently available form. Similarly, U.S. biotechnology inventors have been cut a "ten for one" break on the issue of unity of invention. The immediate potential savings to the industry is in the millions of dollars in Office fees and associated expenses. Finally, the Office seems to signal that it has heard the Federal Circuit on the issue of "written description," but it may be prepared to grant claims that — again — appear to march close against, if not tread over, the sometimes zigging and zagging line drawn by the Federal Circuit.

APPENDIX A:
Examination of Patent Applications Containing Nucleotide Sequences

I. Introduction

Biotechnology is expected to be an important growth industry from now until well into the twenty-first century, particularly in the United States, one which will produce new therapeutics for the benefit of mankind. The Patent and Trademark Office (PTO) has taken a very active role in working together with its customers to simplify and standardize PTO policies and procedures and to encourage and promote the growth of this industry for the benefit of humanity.

For at least a decade, researchers in the biotechnology industry have been filing patent applications claiming isolated DNA or RNA sequences of nucleotides, referred to as nucleotide or nucleic acid sequences. Scientific and technological advances now permit researchers to identify large numbers of gene sequences rapidly. The ease of using automated techniques for sequencing large numbers of nucleotides in a nucleic acid has resulted in the filing of a growing number of patent applications, many of which recite thousands of individual nucleotide sequences with each sequence reciting at least several hundred nucleotides. The examination of these applications presents unprecedented search and examination challenges, even with the most modern, up-to-date equipment.

Faced with these challenges, the PTO held public hearings on issues relating to patent protection of nucleotide sequences on April 16, 1996, in San Diego, California and on April 23, 1996, in Arlington, Virginia. At those hearings, the PTO received several recommendations that restriction practice pursuant to 35 U.S.C. § 121 should be applied to patent applications claiming nucleotide sequences.

This Notice responds to comments received during the hearings. This Notice clarifies PTO’s policy for examination of patent applications that claim large numbers of nucleotide sequences.

II. The PTO Will Permit Applicants to Claim Up to Ten Independent and Distinct Nucleotide Sequences In One National Application

By statute, "[i]f two or more independent and distinct inventions are claimed in one application, the Commissioner may require the application to be restricted to one of the inventions."

35 U.S.C. § 121. Pursuant to this statute, the Rules of Practice in Patent Cases provide that "[i]f two or more independent and distinct inventions are claimed in a single application, the examiner in his action shall require the applicant . . . to elect that invention to which his claim shall be restricted." 37 CFR §1.l42(a). See also 37 CFR §1.141(a).

Nucleotide sequences encoding different proteins are structurally distinct chemical compounds and are unrelated to one another. These sequences are thus deemed to normally constitute independent and distinct inventions within the meaning of 35 U.S.C. § 121. Absent evidence to the contrary, each such nucleotide sequence is presumed to represent an independent and distinct invention, subject to a restriction requirement pursuant to 35 U.S.C. § 121 and 37 CFR §1.141 et seq. Nevertheless, to further aid the biotechnology industry in protecting its intellectual property without creating an undue burden on the Office, the Commissioner has decided sua sponte to partially waive the requirements of 37 CFR §1.141 et seq. and permit a reasonable number of such nucleotide sequences to be claimed in a single application.

Accordingly, in most cases, up to ten (10) independent and distinct nucleotide sequences will be examined in a single application without restriction. It has been determined that normally ten sequences constitute a reasonable number for examination purposes. The PTO believes that allowing applicants to claim up to ten (10) independent and distinct nucleotide sequences in a single application will promote efficient, cost- effective examination of these types of applications. In addition to the specifically selected sequences, those sequences which are patentably indistinct from the selected sequences will also be examined. Furthermore, nucleotide sequences encoding the same protein are not considered to be independent and distinct inventions and will continue to be examined together.

In some exceptional cases, the complex nature of the claimed material, for example a protein amino acid sequence reciting three dimensional folds, may necessitate that the reasonable number of sequences to be selected be less than ten (10). In other cases, applicants may petition pursuant to 37 C.F.R. § 1.181 for examination of additional nucleotide sequences by providing evidence that the different nucleotide sequences do not cover independent and distinct inventions.

III. Under the Unity of Invention Standard in an International Application or National Stage Application Filed Under 35 U.S.C. § 371 Up to Ten Nucleotide Sequences Will Be Searched and/or Examined Without Payment of An Additional Fee

International applications filed under the Patent Cooperation Treaty (PCT) and national stage applications filed under 35 U.S.C. § 371 will be treated in a similar manner. Under 37 CFR §1.475 and §1.499 et seq., when claims do not comply with the requirement of unity of invention, i.e., when the claimed subject matter does not involve "one or more of the same or corresponding special technical features,ö 37 CFR §1.475(a), an additional fee is required to maintain the claims in the same application. 37 CFR §1.476(b).

The Commissioner has decided sua sponte to partially waive 37 CFR §1.475 and §1.499 et seq. to permit applicants to claim up to ten (10) nucleotide sequences which do not have the same or corresponding special technical feature, without the payment of an additional fee. The PCT permits inventions which lack unity of invention to be maintained in the same international application for the payment of additional fees. Thus, in international applications, for each group for which applicant has paid additional international search and/or preliminary examination fees, the PTO has determined that up to four (4) such additional sequences per group is a reasonable number for examination. Further, claims directed to the selected sequences will be examined with claims drawn to any sequence combinations which have a common technical feature with the selected sequences. Nucleotide sequences encoding the same protein are considered to satisfy the unity of invention standard and will continue to be examined together.

IV. Examples of Nucleotide Sequence Claims That Are the Subject of this Notice

Examples of typical nucleotide sequence claims impacted by this Notice include:

(1) an isolated and purified DNA fragment comprising DNA having at least 95% identity

to a DNA sequence selected from SEQ ID Nos. 1- 1,000;

(2) a combination of DNA fragments comprising SEQ ID Nos. 1-1,000; and

(3) a combination of DNA fragments, said combination containing at least thirty

different DNA fragments selected from SEQ ID Nos. 1-1,000.

Applications claiming more than ten (10) individual independent and distinct nucleotide sequences in alternative form, such as set forth in example 1, will be subject to a restriction

requirement. Only the ten (10) nucleotide sequences selected in response to the restriction requirement and any other claimed sequences which are patentably indistinct therefrom will be examined.

Applications claiming only a combination of nucleotide sequences, such as set forth in example 2, will generally not be subject to a restriction requirement. The presence of one novel and

nonobvious sequence within the combination will render the entire combination allowable. The combination will be searched until one nucleotide sequence is found to be allowable. The order of searching will be chosen by the examiner to maximize the identification of an allowable sequence. If no individual nucleotide sequence is found to be allowable, the examiner will consider whether the combination of sequences taken as a whole renders the claim allowable.

Applications containing only composition claims reciting different combinations of individual nucleotide sequences, such as set forth in example 3, will be subject to a restriction requirement. Applicants will be required to select one combination for examination. If the selected combination contains ten or fewer sequences, all of the sequences of the combination will be searched. If the selected combination contains more than ten sequences, the combination will be examined following the procedures set forth above for example 2. More specifically, the combination will be searched until one nucleotide sequence is found to be allowable with the examiner choosing the order of search to maximize the identification of an allowable sequence. The identification of any allowable sequence(s) will cause all combinations containing the allowed sequence(s) to be allowed.

In applications containing all three claims set forth in examples 1-3, the PTO will require restriction of the application to ten sequences for initial examination purposes. Based upon the finding of allowable sequences, claims limited to the allowable sequences as in example 1, all combinations, such as in examples 2 and 3, containing the allowable sequences and any patentably indistinct sequences will be rejoined and allowed.

Rejoinder will be permitted for claims requiring any allowable sequence(s). Any claims which have been restricted and non- selected and which are limited to the allowable sequence(s) will be rejoined and examined.

V. Other Possible Solutions

The PTO is pursuing other possible ways to efficiently examine applications that claim large numbers of nucleotide sequences, including the following:

A. Software Development - Using private contractors, the PTO will attempt to identify, modify or develop software tools to aid in searching and the analysis of search results.

B. Feedback - The PTO will pursue and evaluate suggestions from applicants, members of the bar, industry, scientists, government, and inventors.

C. International Cooperation - The PTO will encourage greater cooperation between the other patent offices of the world in the area of biotechnology. The PTO will work with these offices to share resources thereby minimizing duplication of search and examination.

D. PTO Outside Search Center - The PTO will explore the possibility of establishing an outside search center which would perform standard searches for all patent applicants submitting applications containing nucleotide sequences.

E. Search Standards - The PTO will explore the possibility of establishing quality and proficiency standards for prior art searches so that applicants can perform their own pre-examination searches. Applicants could then submit their searches with their applications, and the PTO could examine applications based on applicants’ searches.

F. Communication - The PTO will communicate its procedures for searching the prior art and how the current hardware and software have been optimized for examination needs.

Any questions, comments or suggestions regarding this Notice should be directed to Esther M. Kepplinger, Supervisory Primary Examiner, Group Art Unit 1302: by mail to Box Comments-Patents, Assistant Commissioner for Patents, Washington, DC 20231; by FAX to (703) 305-3601; or by electronic mail addressed to ekepplin@uspto.gov.

Date: October 17, 1996

Bruce A. Lehman
Assistant Secretary of Commerce and
Commissioner of Patents and Trademarks

APPENDIX B:
Request for Comments on Interim Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112 1 "Written Description" Requirement

AGENCY: Patent and Trademark Office, Commerce.

ACTION: Notice and request for public comments.

SUMMARY: The Patent and Trademark Office (PTO) requests comments from any interested member of the public on the following interim guidelines. These guidelines will be used by PTO personnel in their review of biotechnological patent applications for compliance with the "written description" requirement of 35 U.S.C. §112 ¶1. Although the guidelines are directed primarily to written descriptions of biotechnological inventions, they reflect the current understanding of the PTO and apply across the board to all relevant technologies.

DATES: Written comments on the interim guidelines will be accepted by the PTO until September 14, 1998.

ADDRESSES: Written comments should be addressed to Box 8, Commissioner of Patents and Trademarks, Washington, D.C. 20231, marked to the attention of Scott A. Chambers, Associate Solicitor or to Box Comments, Assistant Commissioner for Patents, Washington, D.C. 20231 marked to the attention of Linda S. Therkorn. Alternatively, comments may be submitted to Scott Chambers via facsimile at (703) 305-9373 or by electronic mail addressed to "scott.chambers@uspto.gov" or to Linda Therkorn via facsimile at (703) 305-8825 or by electronic mail addressed at "linda.therkorn@uspto.gov."

FOR FURTHER INFORMATION CONTACT: Scott Chambers by telephone at (703) 305-9035, by facsimile at (703) 305-9373, by mail to his attention addressed to Box 8, Commissioner of Patents and Trademarks, Washington, D.C. 20231, or by electronic mail at "scott.chambers@uspto.gov"; or Linda Therkorn by telephone at (703) 305-8800, by facsimile at (703) 305-8825, by mail addressed to Box Comments, Assistant Commissioner for Patents, Washington, D.C. 20231, or by electronic mail at "linda.therkorn@uspto.gov."

SUPPLEMENTARY INFORMATION: The PTO requests comments from any interested member of the public on the following interim guidelines. These guidelines will be used by PTO personnel in their review of biotechnological patent applications for compliance with the "written description" requirement of 35 U.S.C. §112 ¶1. Although the guidelines are directed primarily to written descriptions of biotechnological inventions, they reflect the current understanding of the PTO and apply across the board to all relevant technologies. Because these guidelines govern internal practices, they are exempt from notice and comment rulemaking under 5 U.S.C. 553(b)(A).

Written comments should include the following information: 1) name and affiliation of the individual responding; and 2) an indication of whether the comments offered represent views of the respondent’s organization or are they respondent’s personal views. The PTO is particularly interested in comments relating to: 1) the accuracy of the methodology; 2) relevant factors to consider in determining whether the written description requirement of 35 U.S.C. 112 1 is satisfied; 3) whether the scope of these guidelines should be limited to certain technologies, such as biotechnology, or even a particular area of biotechnology such as nucleic acids, or encompass all technologies generally; 4) whether the scope of these guidelines should be expanded to include processes and/or product-by-process claims; and 5) the impact these guidelines may have on currently pending applications as well as future applications.

Parties presenting written comments are requested, where possible, to provide their comments in machine-readable format in addition to a paper copy. Such submissions may be provided by electronic mail messages sent over the Internet, or on a 3.5" floppy disk formatted for use in either a Macintosh, Windows, Windows for Workgroups, Windows 95, Windows NT, or MS-DOS based computer.

Written comments will be available for public inspection on or about September 14, 1998, in Suite 918, Crystal Park 2, 2121 Crystal Drive, Arlington, Virginia. In addition, comments provided in machine-readable format will be available through anonymous file transfer protocol (ftp) via the Internet (address: comments.uspto.gov) and through the World Wide Web (address: www.uspto.gov).

Interim Guidelines for the Examination of Patent Applications Under The 35 U.S.C. §112 ¶1 "Written Description" Requirement

These "Written Description Guidelines" are intended to assist Office personnel in the examination of patent applications for compliance with the written description requirement of 35 U.S.C. 112, 1, in view of University of California v. Eli Lilly1 and the earlier cases Fiers v. Revel and Amgen, Inc. v. Chugai Pharmaceutical Co.3 These Interim Guidelines are directed primarily to determining whether there is written description support for product claims and are not intended to specifically address the description necessary to support process or product-by-process claims. Similarly, these Guidelines are not intended to directly address the question of new matter, which is currently addressed in the Manual of Patent Examining Procedure

2163.06-.07. The Final Guidelines may address these additional issues if public comment suggests they should be addressed. These guidelines are based on the Office’s current understanding of the law and are believed to be fully consistent with binding precedent of the Supreme Court, the Federal Circuit, and the Federal Circuit’s predecessor courts.

These guidelines do not constitute substantive rulemaking and hence do not have the force and effect of law. They are designed to assist Office personnel in analyzing claimed subject matter for compliance with substantive law. Rejections will be based upon the substantive law, and it is these rejections which are appealable. Consequently, any failure by Office personnel to follow the guidelines is neither appealable nor petitionable.

These guidelines are intended to form part of the normal examination process. Thus, where Office personnel establish a prima facie case of lack of written description for a claim, a thorough review of the prior art and examination on the merits for compliance with the other statutory requirements, including those of 35 U.S.C. 101, 102, 103, and 112, is to be conducted prior to completing an Office action which includes a rejection for lack of written description.

Office personnel are to rely on these guidelines in the event of any inconsistent treatment of issues involving the written description requirement between these guidelines and any earlier guidance provided from the Office. Although these guidelines address examples principally drawn from the biotechnological arts, they are intended to be equally applicable to all fields of invention.

I. General Principles Governing Compliance with the "Written Description" Requirement For Applications

The first paragraph of 35 U.S.C. 112 requires that the "specification shall contain a written description of the invention . . . ." This requirement is separate and distinct from the enablement requirement.4 This written description requirement has several policy objectives. "[T]he `essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed."5 Another objective is to put the public in possession of what the applicant claims as the invention. The written description requirement prevents an applicant from claiming subject matter that was not described in the specification as filed, and the proscription against the introduction of new matter in a patent application6 serves to prevent an applicant from adding information that goes beyond the subject matter originally filed.

To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.7 This requirement of the Patent Act promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications for the benefit of the public in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.8

II. Evaluate Whether The Application Complies With the "Written Description" Requirement

The inquiry into whether the description requirement is met must be determined on a case-by-case basis and is a question of fact.9 The examiner has the initial burden of presenting evidence or reasons why a person skilled in the art would not recognize in an applicant’s disclosure a description of the invention defined by the claims.10 Office personnel should adhere to the following procedures when reviewing patent applications for compliance with the written description requirement of 35 U.S.C. 112, 1.

A. Review the entire application to determine what applicant has invented, the field of the inventionand the level of predictability in the art

Prior to determining whether the claims satisfy the written description requirement, Office personnel should review the entire specification, including the specific embodiments, figures, sequence listings, and the claims, to understand what applicant has invented and the correspondence between what applicant has described, i.e., has possession of, and what applicant is claiming. Such a review should be conducted from the standpoint of one of skill in the art at the time the application was filed and should include a determination of the field of the invention and, thus, the level of predictability in the art. Predictability of the structure of a species can be premised upon:

(1) Whether the level of skill in the art leads to a predictability of structure; and/or

(2) Whether teachings in the application or prior art lead to a predictability of structure.

There is an inverse correlation between the level of predictability in the art and the amount of disclosure necessary to satisfy the written description requirement. For example, if there is a well-established correlation between structure and function in the art, one skilled in the art will be able to reasonably predict the complete structure of the claimed invention from its function. Thus, in some factual situations, the written description requirement may be satisfied through disclosure of function alone when there is a well-established correlation between structure and function. In contrast, without such a correlation, prediction of structure from function is highly unlikely. In this latter case, disclosure of function alone will not satisfy the written description requirement.11

B. For each claim, determine what the claim as a whole covers

Each claim must be separately analyzed and given its broadest reasonable interpretation.12 The entire claim, including its preamble language and transitional phrase, must be considered. "Preamble language" is that language in a claim appearing before a transitional phase, e.g., before "comprising," "consisting essentially of," or "consisting of". The transitional term "comprising" (and other comparable terms, e.g., "containing" and "including") is "open-ended"-it covers the expressly recited subject matter alone or in combination with other uns tated subject matter.13 There must be adequate written description to support the claimed invention including the preamble.14 The claim as a whole, including all limitations found in the preamble, the transitional phrase, and the body of the claim, must be described sufficiently to satisfy the written description requirement.15 For claims of the form "A [structure] comprising SEQ ID NO: 1" there may be a written description problem if the claim as a whole, including its preamble and transitional phrase, is directed to an invention of unpredictable structure that is not fully described.

For example, when the term "gene," "mRNA," or "cDNA" is recited in the preamble, it implies a specific structure (or a small genus of specific structures) when used in the traditional sense, i.e., to mean the structure having the naturally occurring sequence. Thus, "A gene comprising SEQ ID NO: 1"; "A mRNA comprising SEQ ID NO: 1"; and "A cDNA comprising SEQ ID NO: 1" implicitly recite specific structures such as promoters, enhancers, coding regions, and other regulatory elements in the preamble which must be sufficiently described in the specification so as to show the applicant was in possession of the claimed inventions.

In contrast, use of less specific, generic preamble language, such as "composition," "nucleic acid," "DNA," and "RNA," does not typically present a written description problem. These terms are sufficiently general that one skilled in the art can readily envision a sufficient number of members of the claimed genus to provide written description support for the genus.

A claim such as "A gene comprising SEQ ID NO: 1," can be viewed as a species claim in which the preamble recites a combination and the body of the claim recites a subcombination: The "gene" is the combination and "SEQ ID NO: 1" (which is a fragment of the gene) is the subcombination. Written description of only the subcombination (in this example the fragment SEQ ID NO: 1) normally does not put one in possession of the combination (in this example the gene).

Likewise, generic claims to sequences can be viewed as a genus of such combination-subcombination claims. For example, a claim such as "A nucleic acid comprising SEQ ID NO: 1" can be viewed as a genus claim in which each member of the genus (each species) is itself a combination-subcombination: Each member of the genus "nucleic acid" is a combination containing the subcombination "SEQ ID NO: 1" (which is a fragment of the nucleic acid). Again, the generic term "nucleic acid" does not typically present a written description problem because one skilled in the art can readily envision a sufficient number of members of the claimed genus to provide written description support for the genus.16

C. For each claimed species, determine whether there is sufficient written description to inform a skilled artisan that applicant was in possession of the claimed invention at the time the application was filed

Written description may be satisfied through disclosure of relevant identifying characteristics, i.e., structure, other physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.17 What is well known to one skilled in the art need not be disclosed.18 If a skilled artisan would have understood the inventor to be in possession of the claimed invention at the time of filing, even if every nuance of the claims is not explicitly described in the specification, then the adequate description requirement is met.19

For each claimed species:

(1) Determine whether a complete structure is disclosed. The complete structure of a species typically satisfies the requirement that the description be set forth in "such full, clear, concise and exact terms" to show possession of the claimed invention.20 If a complete structure is disclosed, the written description requirement is satisfied for that species, and a rejection under 35 U.S.C. 112 1 for lack of written description must not be made.

For example, consider the following claim:

A probe for use in detecting nucleic acid sequences coding for enzyme Q from the genus Bacillus consisting of SEQ ID NO: 16.21

Considering the claim as a whole, it is a species claim covering the probe SEQ ID NO: 16.The specification discloses the complete sequence for SEQ ID NO: 16.Thus, this claim falls into the "safe harbor" described under C(1).

(2) If the complete structure is not disclosed, determine whether the specification discloses other relevant identifying characteristics, i.e., physical and/or chemical characteristics and/or functional characteristics coupled with a known or disclosed correlation between function and structure, sufficient to describe the claimed invention in such full, clear, concise and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. Disclosure of any combination of such identifying characteristics that would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient. In such a case, a rejection for lack of written description under 35 U.S.C. §112 ¶1 must not be made.

For example, consider the following claim:

An isolated double-stranded DNA consisting of (1) a single- stranded DNA which has a molecular size of 2.57 Kb and is derived from golden mosaic virus, and (2) a DNA complementary to said single-stranded DNA, giving the restriction endonuclease cleavage map shown in FIG.2(a) and having no Mbo I restriction endonuclease site.

Although the specification does not disclose the complete structure for the claimed DNA, it does disclose sufficient identifying characteristics, i.e., size, cleavage map, and source from which the DNA is derived. Thus, while this claim does not meet the C(1) criteria because the complete sequence is not disclosed, it does meet the C(2) criteria because one skilled in the art would recognize from the characteristics, e.g., size, map, source, that applicant was in possession of the claimed material at the time of filing.

The following protein claim also falls within the C(2) criteria:

An isolated alginate lyase enzyme wherein said enzyme lyses alginate in the mucous substance produced in a patient with cystic fibrosis and wherein said enzyme has the N-terminal amino acid sequence SEQ ID No. 1, obtained from Flavobacterium pepermentium and has the following physicochemical properties: (1) Activity: lyses alginate to saccharides having a non-reducing end C4-C5 double bond and ultimately to 4-deoxy-5-ketouronic acid; (2) Molecular weight: 60,000 daltons; (3) Optimal pH: 8.0; (4) Stable pH: 6.0-8.0; (5) Optimal temperature: 70 degrees C; and (6) Substrate specificity: alginate.

In this example, the specification discloses the molecular weight, origin, activity, and specificity but does not disclose the complete structure for the claimed enzyme. Thus, this claim would not meet the C(1) criteria because the complete sequence is not disclosed. However, the claim meets the C(2) criteria because, although the complete structure is not disclosed, one skilled in the art would recognize from the disclosed physical characteristics-e.g., molecular weight, origin, activity, and specificity-that applicant was in possession of the claimed material at the time of filing.

In contrast, consider the following claim:

An isolated nucleotide sequence consisting of the sequence of the reverse transcript of a human mRNA, which mRNA encodes insulin.

The specification in this example provides the coding sequence for rat insulin but not that for human insulin. The description for the reverse transcript of human mRNA is limited to its function, encoding human insulin, and to a method for isolating the claimed sequence from its natural source. A sequence described only by a purely functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed species. In this case, even though a genetic code table would correlate a known insulin amino acid sequence with a genus of coding nucleic acids, the same table cannot predict the native, naturally occurring nucleic acid sequence of human mRNA or its corresponding cDNA. Thus, the specification in this example does not provide adequate written description, either under the C(1) or C(2) criteria.22

Any claim to a species that does not meet the test described under C(1) or C(2) must be rejected as lacking adequate written description under 35 U.S.C. §112 ¶1.

D. For each claimed genus, determine whether there is sufficient written description to inform a skilled artisan that applicant was in possession of the claimed genus at the time the application was filed

The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by relevant identifying characteristics, i.e., structure or other physical and/or chemical characteristics, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.23 A "representative number of species" requires that the species which are expressly described be representative of the entire genus. Thus, when there is substantial variation within the genus, it may require a description of the various species which reflect the variation within the genus. For example, a broadly drawn claim to a specific gene from ruminant mammals may require a representative species from cattle, buffalo, bison, goat, deer, antelope, camel, giraffe and llama.

What constitutes a "representative number" is an inverse function of the predictability of the art, as determined in IIA above. The number must be sufficient to reasonably identify the other members of genus. In an unpredictable art, adequate written description of a genus cannot be achieved by disclosing only one species within the genus. In fact, if the members of the genus are expected to vary widely in their identifying characteristics, such as structure and activity, written description for each member within the genus may be necessary.

Generalized descriptions alone, such as "vertebrate insulin cDNA" or "mammalian insulin cDNA," fail to satisfy the written description requirement because they do not describe any members of the genus except by function without any known or disclosed correlation between function and structure.24 If the correlation between structure and function in the art would not have been known to one skilled in the art and the specification does not describe the correlation, the written descriptive support cannot depend on that correlation.

For each claim to a genus:

(1) Determine whether a representative number of species have been described by complete structure as in C(1) above.If a representative number have been so described, then the applicant has written description support for the claimed genus and a rejection under §112 ¶1 for lack of written description must not be made.

For example, consider the following claim to a genus:

An isolated DNA probe for detecting HIV-X, wherein said DNA probe hybridizes to the nucleotide sequence set forth in SEQ ID NO:1 under the following conditions: hybridization in 7% sodium dodecyl sulfate (SDS), 0.5M NaPO4 pH 7.0, 1mM EDTA at 50 C.; and washing with 1% SDS at 42 C.

In this case, the specification discloses the sequence of the isolated DNA molecule consisting of SEQ ID NO: 1 and discloses several sequences that hybridize to SEQ ID NO: 1. Hybridization under the stringent conditions specified here requires that the claimed nucleic acid probes be structurally similar to the complement of the nucleic acid sequence disclosed as SEQ ID NO: 1. In this case, the description as a whole is sufficient to evidence possession of the claimed genus because the genus is defined by relation to the structure of the sequence provided as SEQ ID NO: 1, and because several species are disclosed that possess the hybridization property which further defines the genus. Thus, this claim to a genus meets the D(1) criteria.

(2) For each claim to a genus not supported as described under D(1), determine whether there is a representative number of adequately described species, as analyzed under C(2). The representative number must permit one skilled in the art to reasonably identify the remaining members of the genus. If a representative number are so described, then the written description requirement is satisfied and, again, a rejection under §112 ¶1 for lack of written description must not be made.

For example, consider the following claim to a genus:

A monoclonal antibody which specifically binds to the novel cancer associated TAG-31 antigen but which does not substantially bind normal adult human tissues, wherein said monoclonal antibody has a binding affinity of greater than 3 times 109 M-1 for TAG-31.

Considering the claim as a whole, it is drawn to a genus of monoclonal antibodies. Although the specification does not disclose the complete structure of a representative number of species to support the claimed genus of antibodies, it does disclose multiple monoclonal antibodies which have the isotype claimed as well as the binding specificity and binding affinity characteristics recited in the claims. In this well-developed art, additional identifying characteristics for a substantial portion of the genus are well-known (e.g., number of chains, disulfide bonds, constant and variable regions, etc.). Thus, applicant’s disclosure combined with what was known in the art are sufficient to describe the claimed genus of monoclonal antibodies in such full, clear, concise and exact terms to show applicant was in possession of the claimed antibodies. Thus, the claim meets the D(2) criteria.

As another example, consider the following claim to a genus:

An isolated mutanase enzyme produced by Bacillus having the following physicochemical properties (1) to (9): (1) action: an ability to cleave alpha-1,3-glucosidic links of mutan; (2) substrate specificity: an ability to effectively decompose mutan;(3) optimum pH: pH 4 to 4.5 when reacting on a mutan substrate at 35 degrees C. for 10 minutes; (4) pH range for stability: pH 4 to 10 when kept at 25 degrees C for 24 hours; (5) optimum temperature: 50 degrees to 65 degrees C when reacted at pH 5 with mutan as a substrate; (6) thermal stability: enzyme activity remains stable below 50 degrees C after incubation at pH 5 for 10 minutes; (7) effect of metal ions: mercury and silver show inhibitory effect on a mutan substrate; (8) effect of inhibitors: p-chloromercurybenzoic acid shows inhibitory effect on a mutan substrate; and (9) molecular weight: about 140,000 to about 160,000 as determined by SDS-polyacrylamide gel electrophoresis.

Considering the claim as a whole, it covers a genus of mutanase enzymes. Although the specification does not disclose the complete structure of a representative number of species to support the claimed genus of enzyme compositions, it does disclose 3 mutanase species produced by different strains of Bacillus (mutanases A, B and C) which are identified by multiple relevant identifying characteristics, i.e., molecular weight, substrate specificity, optimum and ranges of temperature and pH for mutan cleavage activity, etc. In this well-developed art, these identifying characteristics are sufficient for a skilled artisan to recognize applicant had possession of the species from the identifying characteristics of the three mutanase species, to reasonably predict sufficient identifying characteristics of the other members of the genus and, thus, establish possession of the genus. Thus, the claim meets the D(2) criteria.

As another example, consider the following claim to a genus:

A DNA comprising a novel DF3 enhancer and DNA encoding a heterologous gene but not encoding DF3 wherein said DF3 enhancer consists of SEQ ID NO: 1.

Considering the claim as a whole, it covers a genus of DNA. The specification does not describe a representative number of members of the genus by complete structure. Thus, the claim does not meet the D(1) criteria. However, there is sufficient disclosure of identifying characteristics common to the members of the genus, i.e., DF3 enhancer, to meet the D(2) criteria. Because of the nature of the generic term "DNA," one skilled in the art could envision a sufficient number of the members of the genus to describe the invention in such full, clear and concise terms as to show possession of the invention at the time of filing.

In contrast, consider the claim:

An isolated nucleic acid comprising the structure of the reverse transcript of a mammalian mRNA, which mRNA encodes insulin.

Considering the claim as a whole, the claim covers the genus of nucleotide sequences encoding mammalian insulin. The specification only provides the coding sequence for rat insulin cDNA and a method to isolate the coding sequence from its natural source.25 This description does not meet the criteria of D(1) or D(2) and thus does not satisfy the written description requirement.

Also contrast the claim "A gene comprising SEQ ID NO: 1." Although all genes encompassed by this claim share the characteristic of comprising SEQ ID NO: 1, and as such might appear to meet the D(2) criteria, there is insufficient description of the characteristics (e.g., promoters, enhancers, coding regions, and other regulatory elements) which identify the genes, as opposed to any DNA comprising SEQ ID NO: 1.

If sufficient identifying characteristics are not disclosed for a given genus, as described in D(1) or D(2), the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. §112 ¶1.

III. Complete Patentability Determination Under All Statutory Requirements and Clearly Communicate Findings, Conclusions and Their Bases

The above only describes how to determine whether the written description requirement of 35 U.S.C. 112 1 is satisfied. Regardless of the outcome of that determination, Office personnel must complete the patentability determination under all the relevant statutory provisions of the Patent Act.

Once Office personnel have concluded analysis of the claimed invention under all the statutory provisions, including 35 U.S.C. 101, 112, 102 and 103, they should review all the proposed rejections and their bases to confirm their correctness. Only then should any rejection be imposed in an Office action. The Office action should clearly communicate the findings, conclusions and reasons which support them.

Specific to these guidelines:

A. For each claim lacking written description support, reject the claim under section 112, 1, for lack of adequate written description

In rejecting a claim, set forth express findings of fact regarding the above analysis which support the lack of written description conclusion. These findings should:

(1) identify the claim limitation not described; and

(2) provide reasons why a person skilled in the art at the time the application was filed would not have recognized the description of this limitation in view of the disclosure of the application as filed.

When appropriate, suggest amendments to the claims which would bring the claims into compliance with the written description in the specification, bearing in mind the prohibition against new matter in the claims and corresponding description set forth in 35 U.S.C. 112 and 132.

B. Upon reply by applicant, again determine the patentability of the claimed invention, including whether the written description requirement is satisfied by performing the analysis described above in view of the whole record

Upon reply by applicant, before repeating any rejection under Section 112 ¶1 for lack of written descriptive basis, review the basis for the rejection in view of the record as a whole, including amendments, arguments and any evidence submitted by applicant. If the whole record now demonstrates that the written description requirement is satisfied, do not repeat the rejection in the next Office action. If the record still does not demonstrate that written description is adequate to support the claim(s), repeat the rejection under 35 U.S.C. 112 1, fully respond to applicant’s rebuttal arguments, and properly treat any further showings submitted by applicant in the reply. Any affidavits, including those relevant to the §112 ¶1 written description requirement, must be thoroughly analyzed and discussed in the Office action.

ENDNOTES (References from Appendices A and B):

1. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997).

2. 984 F.2d 1164, 25 USPQ2d 1601 (Fed. Cir. 1993).

3. 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991).

4. E.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1560, 19 USPQ2d 1111, 1115 (Fed. Cir. 1991).

5. In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977).

6. 35 U.S.C. §132 & §251.

7. E.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563, 19 USPQ2d 1111, 1116 (Fed. Cir. 1991). Much of the written description case law addresses whether the specification as originally filed supports claims not originally in the application. The issue raised in the cases is most often phrased as whether the original application provides "adequate support" for the claims at issue or whether the material added to the specification incorporates "new matter" in violation of 35 U.S.C. 132. The "written description" question similarly arises in the interference context, where the issue is whether the specification of one party to the interference can support the newly added claims corresponding to the count at issue, i.e., whether that party can "make the claim" corresponding to the interference count. E.g., see Martin v. Mayer, 823 F.2d 500, 502, 3 USPQ2d 1333, 1335 (Fed. Cir. 1987).

In addition, early opinions suggest the Patent and Trademark Office was unwilling to find written descriptive support when the only description was found in the claims; however, this viewpoint was rejected. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980) (original claims constitute their own description); In re Gardner, 475 F.2d 1389, 177 USPQ 396 (CCPA 1973) (accord); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) (accord). It is now well-accepted that a satisfactory description can be mined from the claims or any other portion of the originally filed specification.

These early opinions did not address the quality or specificity of particularity that was required in the description, i.e., how much description is enough.

8. See Eli Lilly, 119 F.3d at 1566, 43 USPQ2d at 1404.

9. See In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) ("Precisely how close [to the claimed invention] the description must come to comply with 112 must be left to a case-by-case development."); In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976) (inquiry is primarily factual and depends on the nature of the invention and the amount of knowledge imparted to those skilled in the art by the disclosure).

10. Wertheim, 541 F.2d at 262, 191 USPQ at 96.

11. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate").

12. See, e.g., In re Morris, 127 F.3d 1048, 1053-54, 44 USPQ2d 1023, 1027 (Fed. Cir. 1997).

13. See, e.g., Ex parte Davis, 80 USPQ 448, 450 (1948) ("comprising" leaves the "claim open for the inclusion of unspecified ingredients even in major amounts".), quoted with approval in Moleculon Research Corp v. CBS, Inc., 793 F.2d 1261, 1271, 229 USPQ 805, 812 (Fed. Cir. 1986).

14. See Pac-Tec Inc. v. Amerace Corp., 903 F.2d 796, 801, 14 USPQ2d 1871, 1876 (Fed. Cir. 1990) (determining that preamble language that constitutes a structural limitation is actually part of the claimed invention).

15. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997).

16. E.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1405-06.

17. A "relevant identifying characteristic" is one that would provide evidence that applicant was in possession of what is claimed. For example, the presence of a restriction enzyme map of a gene may be relevant to a statement that the gene has been isolated. One skilled in the art could determine whether the gene disclosed was the same as or different than a gene isolated by another by comparing the restriction enzyme map. In contrast, evidence that the gene could be digested with a nuclease would not normally represent a relevant characteristic since any gene would be digested with a nuclease.

Examples of identifying characteristics include a sequence, structure, binding affinity, binding specificity, molecular weight and length. Although structural formulas provide a convenient method of demonstrating possession of specific molecules, other identifying characteristics can demonstrate the requisite possession. For example, unique cleavage by particular enzymes, isoelectric points of fragments, detailed restriction enzyme maps, a comparison of enzymatic activities, or antibody cross reactivity may be sufficient to show possession of the claimed invention to one of skill in the art. See Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997) ("written description" requirement may be satisfied by using "such descriptive means as words, structures, figures, diagrams, formulas, etc. that fully set forth the claimed invention").

However, a definition by function alone "does not suffice" to sufficiently describe a coding sequence "because it is only an indication of what the gene does, rather than what it is." Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406. See also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen).

18. See Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986).

19. See, e.g., Vas-Cath, 935 F.2d at 1563, 19 USPQ2d at 1116; Martin v. Johnson, 454 F.2d 746, 751, 172 USPQ 391, 395 (CCPA 1972) (stating "the description need not be in ipsis verbis to be sufficient").

20. 35 U.S.C. §112 ¶1. Cf. Fields v. Conover, 443 F.2d 1386, 1392, 170 USPQ 276, 280 (CCPA 1971) (finding a lack of written description because the specification lacked the "full, clear, concise, and exact written description" which is necessary to support the claimed invention).

21. The examples contained within these guidelines are not intended to represent the minimum requirements necessary to comply with 35 U.S.C. §112 ¶1.

22. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.

23. See id. at 1568, 43 USPQ2d at 1406.

24. Cf. Eli Lilly, 119 F.3d at 1567, 43 USPQ2d at 1405 (stating that "The name cDNA is not itself a written description of that DNA; it conveys no distinguishing information concerning itself.").

25. See id. 1568, 43 USPQ2d at 1406.

June 9, 1998

BRUCE A. LEHMAN
Assistant Secretary of Commerce and
Commissioner of Patents and Trademarks
DEPARTMENT OF COMMERCE
Patent and Trademark Office
[Docket No. 980605148-8148-01]

FOOTNOTES

(1) This practice is codified in 37 C.F.R. §1.475:

Unity of invention before the International Searching Authority, the International Preliminary Examining Authority and during the national stage.
(a) An international and a national stage application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept ("requirement of unity of invention"). Where a group of inventions is claimed in an application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression "special technical features" shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.
(b) An international or a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories:

(1) A product and a process specially adapted for the manufacture of said product; or
(2) A product and a process of use of said product; or
(3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or
(4) A process and an apparatus or means specifically designed for carrying out the said process; or
(5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process.

(2) This is explicitly stated in the Commissioner's Notice:
The Commissioner has decided sua sponte to partially waive 37 C.F.R. §1.475 and §1.499 et seq. to permit applicants to claim up to ten (10) nucleotide sequences which do not have the same or corresponding special technical feature, without the payment of an additional fee. The PCT permits inventions which lack unity of invention to be maintained in the same international application for the payment of additional fees. Thus, in international applications, for each group for which applicant has paid additional international search and/or preliminary examination fees, the PTO has determined that up to four (4) such additional sequences per group is a reasonable number for examination. Further, claims directed to the selected sequences will be examined with claims drawn to any sequence combinations which have a common technical feature with the selected sequences. Nucleotide sequences encoding the same protein are considered to satisfy the unity of invention standard and will continue to be examined together.

(3) In re Brana, 51 F.3d 1560, 34 U.S.P.Q.2d 1436 (Fed. Cir. 1995).

(4) Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (C.C.P.A. 1980). Although the Brana court did not expressly rely on this case, it is extensively relied upon in the guidelines. (5) Doll, John, "The Patenting of DNA, Science Magazine, Volume 280, Number 5364 (May 1, 1998), p. 689.

(6) U.S. patent applications 07/716,831, filed June 21, 1991, 07/837,195, filed September 25, 1992, and 07/952,911, filed February 12, 1993, all filed in the name of Craig Venter, et al. and assigned to the National Institutes of Health.

(7) See Rebecca S. Eisenberg and Robert P. Merges, "Opinion Letter as to the Patentability of Certain Inventions Associated with the Identification of Partial cDNA Sequences," 23 AIPLA Q. J. 1 (1995).

(8) This potential defect could, theoretically, be avoided by adding a further limitation:

A protein, except as existing or occurring in nature, comprising:
(A) all or part of the amino acid sequence set forth in SEQ. ID. NOS. 1, 2 or 3;
(B) an amino acid sequence at least 50% homologous with an amino acid sequence defined in (A), said protein having the in vivo biological property of stimulating the production of enzyme Y, and said protein having an amino acid sequence which differs from the sequence of any known polypeptide.
In other words, the inventor here is effectively seeking to claim any non-naturally occurring, non-biologically inactive, non-anticipated, enzyme Y-inhibiting protein.

(9) In re Fisher, 314 F.2d 817, 137 U.S.P.Q. 150 (C.C.P.A. 1963).

(10) Young v. United States, 179 U.S.P.Q. 801 (US Cl. Ct 1973):

Moreover, a single means-plus-function claim does not particularly point out and distinctly claim the invention as required by paragraph 1 of § 112, since it fails to recite any structure whatsoever. As stated in Ex parte Bullock, 1907 C.D. 93, 127 O.G. 580, a "single means" claim:
... is clearly indefinite and functional. No structure by which the function stated is accomplished is set forth in the claim. The claim is not for a combination of which the "means" for the purpose mentioned is an element, but is merely for means as an element and covers all possible means for accomplishing a certain function regardless of structure.
179 U.S.P.Q. at 808.

(11) See Genentech v. Wellcome
The independent claims at issue in the '075 and '330 recombinant patents contain no definition for the DNA isolate other than that it encodes human t-PA. Such a claim, defining a substance only by its function, encompassing all substances that accomplish that result, is akin to a single means claim, which might fail to satisfy the definiteness requirement of 35 U.S.C Section 112.
31 U.S.P.Q. 1172.

Fiers v. Revel
Because the count at issue purports to cover all DNAs that code for b-IF, it is also analogous to a single means claim, which has been held not to comply with the first paragraph of section 112.
25 U.S.P.Q. 1606.

In re Hyatt
The long-recognized problem with a single means claim is that it covers every conceivable means for achieving the stated result, while the specification discloses at most only those means known to the inventor. See O'Reilly v. Morse, 56 U.S. 62, 112 (1853). Thus, the claim is properly rejected for what used to be known as "undue breadth," but has since been appreciated as being, more accurately, based on the first paragraph of §112.
218 U.S.P.Q. 197.

In Hyatt, the objectionable claim read:
A Fourier transform processor for generating Fourier transformed incremental output signals in response to incremental input signals, said Fourier transform processor comprising: incremental means for incrementally generating the Fourier transformed incremental output signals in response to the incremental input signals.

(12) Fiers v. Revel, 984 F.2d 1164,25 U.S.P.Q.2d 1601 (Fed. Cir. 1993).

(13) A means-plus-function claim has at least the following statutory advantages under U.S. patent law:
- A written description is inherently present, as long as at least one corresponding structure for each means is found in the patent specification.
- Enablement for the full scope of the claim is necessarily present, so long as at least one corresponding embodiment in the specification is enabled.
- The claim is definite, notwithstanding that it literally encompasses both disclosed structures and "equivalent structures" that are not expressly defined in the patent specification.
- The claim can be enforced both literally and under the doctrine of equivalents, further expanding the claim to subject matter performing substantially the same function in substantially the same way to achieve substantially the same result.

(14) A proper "means-plus-function" claim format would appear on its face to be relatively easy to perfect for DNA, i.e., a claim to a combination of two or more functionally-defined DNA sequence limitations. Consider the following claim format:
An isolated DNA compound useful for expressing a protein characterized by:
- a first sequence of DNA bases constituting a means for encoding a polypeptide that is effective to stimulate enzyme Y in vivo and
- a second sequence of DNA bases, operatively positioned with respect to said first sequence, constituting a means for promoting expression of said first sequence.

This claim ­ according to 35 U.S.C. § 112, sixth paragraph ­ reads both DNA for expressing the disclosed proteins, SEQ. ID. NOS. 1, 2, and 3 ­ as well as equivalent structures performing the same function.

(15) A corresponding protein product claim can be fashioned from the DNA claim, at least in product-by-process terms:
A protein product of the process of expression in a transfected cell of an isolated DNA compound characterized by:
- a first sequence of DNA bases constituting a means for encoding a polypeptide that is effective to stimulate enzyme Y in vivo and
- a second sequence of DNA bases, operatively positioned with respect to said first sequence, constituting a means for promoting expression of said first sequence.

(16) 63 Fed. Reg. 32639-32645 (June 15, 1998).

(17) University of California v. Eli Lilly and Co., 43 U.S.P.Q.2d 1398, 119 F.3d 1559 (Fed. Cir. 1997). The district court decision is reported at 39 U.S.P.Q.2d 1225 (DC S.Ind. 1995).

(18) Doll offered an economic rationale for broad patent claims in addition to the legal analysis. The economic rationale appeared as follows:
However, in the USPTO's view, new areas of technology do not create the need for a whole new specialized patent law. In many ways, the arguments currently being used for DNA sequence technology resemble those voiced 30 to 40 years ago when polymer chemistry was an emerging technology. At that time, people argued that if broad generic claims were granted on the building blocks of basic polymers, it would devastate the industry. In fact, no such disaster occurred. For example, the issuing in 1965 of a basic patent broadly claiming a vulcanizable copolymer of aliphatic mono-olefins and unsaturated bridged-ring hydrocarbons (3) did not preclude the later issuing of patents to different inventors for several copolymers of this type (4). These patents represent early examples of ethylene-propylene-diene monomer (EPDM) rubbers, which are highly weather- and ozone-resistant, stable to thermal aging, and have good electrical insulating properties. These EPDM rubbers have been commercially important as components in tires, weather stripping, radiator hoses, wire insulation, impact modifiers, and roofing.
EPDM copolymers were assembled from three basic building blocks that could be combined in many different ways and, as such, generic and specific claims to these copolymers are analogous to claims that may be issued to DNA inventions. Just as the issuing of broad product claims at the early stages of this technology did not deter development of other new vulcanizable copolymers, the issuing of relatively broad claims in genomic technology should not deter inventions in genomics. Two relevant examples of this in the field of biotechnology are the polymerase chain reaction (PCR) and the human immunodeficiency virus (HIV) protease, which were patented and then widely licensed to permit the biotech industry to continue to grow and benefit from these inventions.
Again, the comparisons being drawn are inapt. The monomers were chemical compounds, vended as chemical compounds. The persons owning patents on these compounds and their uses were clearly entitled to patents; the inventions they made were starting materials or intermediates that were used in a variety of useful end products. EST's, in contrast, are neither. They are £ at best ­ a part of the structure of a compound that might later be discovered and used as one means of making a protein product yet to be identified. (19) The appealed claim read in full: 4. An adrenocorticotrophic hormone preparation containing at least 1 International Unit of ACTH per milligram and containing no more than 0.08 units of vasopressin and no more than 0.05 units of oxytocin per International Unit of ACTH, and being further characterized as containing as the active component of [a?] polypeptide of at least 24 amino acids having the following sequence from the N terminus of the molecule; Serine, Tyrosine, Serine, Methionine, Glutamic Acid, Histadine, Phenylalanine, Arginine, Tryptophan, Glycine, Lysine, Proline, Valine, Glycine, Lysine, Lysine, Arginine, Arginine, Proline, Valine, Lysine, Valine, Tyrosine, Proline. [Emphasis supplied.]