ZYMEWORKS INC.Download PDFPatent Trials and Appeals BoardNov 23, 20202020002488 (P.T.A.B. Nov. 23, 2020) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 14/409,419 12/18/2014 Gregory Lakatos 069480-5010-US 4037 43850 7590 11/23/2020 Morgan, Lewis & Bockius LLP (SF) One Market, Spear Street Tower, Suite 2800 San Francisco, CA 94105 EXAMINER BORIN, MICHAEL L ART UNIT PAPER NUMBER 1631 NOTIFICATION DATE DELIVERY MODE 11/23/2020 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): donald.mixon@morganlewis.com sfipdocketing@morganlewis.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte GREGORY LAKATOS and SURJIT BHIMARAO DIXIT1 Appeal 2020-002488 Application 14/409,419 Technology Center 1600 Before DONALD E. ADAMS, ERIC B. GRIMES, and FRANCISCO C. PRATS, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a method of modeling the effect of a mutation on a polypeptide, which have been rejected as being ineligible for patenting. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 Appellant identifies the real party in interest as Zymeworks, Inc. Appeal Br. 3. We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appeal 2020-002488 Application 14/409,419 2 STATEMENT OF THE CASE The Specification states that [p]rotein engineering frequently involves investigating the properties of a known wild-type sequence, making mutations in a protein of known sequence and structure, and evaluating the effects of these mutations on properties such as protein fold stability, or protein binding. An understanding of the thermodynamically relevant structural configurations of the wild-type and mutated proteins is beneficial when evaluating the effects of such mutations. Spec. ¶ 4. The Specification describes systems and methods for identifying the thermodynamically relevant configurations of a polymer or polymer region. The systems and methods combine configurational sampling and structural clustering algorithms in novel ways to identify sets of polymer configurations that are mutually distinct, and have free energies close to the thermodynamic ground state. Id. ¶ 15. Claims 1, 4, 5, 7, 9–15, 18, 19, 22, 23, 27–30, 36, 38, 40, 41, 44, and 45 are on appeal. Claim 1, reproduced below, is illustrative: 1. A method of evaluating an effect that a mutation of a polypeptide of known sequence and structure has on the polypeptide by identifying one or more conformations for the polypeptide upon incorporation of the mutation, wherein the polypeptide comprises a plurality of atoms, and wherein the polypeptide comprises at least one contiguous segment of main chain, the method comprising: at a computer system having one or more processors and memory storing one or more programs to be executed by the one of more processors: (A) obtaining an initial set of three-dimensional coordinates {x1, ..., xN} for the polypeptide, wherein each respective xi in {x1, ..., Appeal 2020-002488 Application 14/409,419 3 xN} is a three dimensional coordinate for an atom in the plurality of atoms in said polypeptide; (B) identifying, in silico, a residue of the polypeptide, and replacing the residue with a different residue, thereby defining a sequence of a mutated polypeptide; (C) identifying a region of the polypeptide based upon the identity of the replaced residue of the mutated polypeptide, the region comprising a plurality of residues; (D) altering a side-chain rotamer conformation, with respect to the initial set of three-dimensional coordinates {x1, ..., xN} of each residue in a subset of residues in the region of the polypeptide, for each respective subset of residues in the region of the polypeptide in a plurality of subsets of residues in the region of the polypeptide, thereby deriving a plurality of mutated polypeptide structures of the region of the polypeptide, wherein each respective subset of residues in the plurality of subsets of residues in the region of the polypeptide is selected from among all the residues in the region of the polypeptide using a deterministic, randomized or pseudo-randomized algorithm; (E) generating a plurality of sets of clusters for each respective residue in the region of the polypeptide, using the plurality of mutated polypeptide structures derived in (D), wherein each respective set of clusters in the plurality of sets of clusters is for (i) a side chain or a main chain of a respective residue in the region of the polypeptide in which each respective cluster in the respective set of clusters is formed by clustering a conformation of the side chain or main chain of the respective residue in each mutated polypeptide structure in the plurality of mutated polypeptide structures derived in (D) or (ii) a contiguous segment of the main chain in the at least one contiguous segment of main chain in the region of the polypeptide in which each respective cluster in the respective set of clusters is formed by clustering a structural metric associated with the main chain of the contiguous segment of the Appeal 2020-002488 Application 14/409,419 4 main chain in each mutated polypeptide structure in the plurality of mutated polypeptide structures derived in (D); (F) grouping respective mutated polypeptide structures in the plurality of mutated polypeptide structures into a plurality of subgroups, wherein each mutated polypeptide structure in a subgroup in the plurality of subgroups falls into the same cluster in a threshold number of the sets of clusters in the plurality of sets of clusters; and (G) determining a free energy estimate or configurational entropy of a plurality of mutated polypeptide structures in each subgroup in the plurality of subgroups, thereby identifying the effect that the mutation of the polypeptide has on the polypeptide in the form of the free energy estimate or the configurational entropy in each subgroup in the plurality of subgroups. Claims 44 and 45 are also independent. Claim 44 is directed to a computer system comprising memory storing at least one program and instructions for carrying out the steps described in claim 1. Claim 45 is directed to a computer readable storage medium storing a computational model comprising instructions for carrying out the steps recited in claim 1. OPINION Claims 1, 4, 5, 7, 9–15, 18, 19, 22, 23, 27–30, 36, 38, 40, 41, 44, and 452 stand rejected under 35 U.S.C. § 101 on the basis that “the claimed invention is directed to non-statutory subject matter.” Ans. 3. The Examiner finds that the claims recite an abstract idea in the form of mathematical concepts and/or a mental process. Id. at 4. 2 The statement of the rejection omits claim 36 and includes claim 39. Ans. 3. However, claim 39 has been canceled and the Examiner has indicated that no claims are allowable. See Amdt. filed May 23, 2018; Final Action 1. Thus, we understand the rejection to apply to all of the pending claims, including claim 36. Appeal 2020-002488 Application 14/409,419 5 More specifically, the Examiner finds that [s]teps drawn to a mental process recited in the claims include [(]A) obtaining an initial set of three-dimensional coordinates; (B) identifying a residue of the polypeptide, and replacing the residue with a different residue; (C) identifying a region of the polypeptide; (D) altering a side-chain rotamer conformation, [t]hereby deriving a plurality of mutated polypeptide structures of the region of the polypeptide; (E) generating a plurality of sets of clusters; (F) grouping polypeptide structures into a plurality of subgroups; and (G) determining a free energy estimate or configurational entropy. Id. at 5. The Examiner reasons that “[t]he steps are able to be performed in the mind, but for the recitation of the computer system. . . . [N]othing in the claim element precludes the step from practically being performed in the human mind.” Id. The Examiner also finds that “[m]athematical concepts recited in the claims include ‘determining a free energy estimate or configurational entropy’” because the Specification “indicate[s] that the determination of the claimed values is a matter of mathematical computation.” Id. at 6. The Examiner finds that the recited abstract ideas are not integrated into a practical application because “[t]here are no positive process limitations recited in the claim for actually using the information produced by the abstract idea outside of the computer (e.g. a real-world practical application or solution to a problem)” and “using a processor to perform the Appeal 2020-002488 Application 14/409,419 6 method steps amounts to no more than mere instructions to apply the exception using a generic computer component.” Id. at 6–7. Finally, the Examiner finds that the claimed method “merely requires generic computer implementation. . . . Therefore, the claims as a whole do not provide significantly more than a generic computer upon which the claimed method steps are executed.” Id. at 8. Appellant argues that “[t]he limitations of claim 1 are not directed to mere mathematical relationships, mathematical formulas or equations, or mathematical calculations.” Appeal Br. 13. Appellant also argues that “a person of skill in the art would understand that the claimed steps . . . cannot, as a practical matter, be performed in a human mind. Indeed, the entire field of protein modeling and engineering became possible with the advent of computing technologies.” Id. Appellant also argues that “the additional elements [of claim 1] in combination provide an improvement to a technical field or technical fields, namely, protein engineering. Indeed, claim 1 embodies a specific, meaningful way that provides an improvement in the field of rational protein design and modeling.” Id. at 14. That is, the “claims are focused on a specific solution to a problem in the rational protein design and modeling arts—i.e., that conventional methods evaluating an effect that a mutation of a polypeptide of known sequence and structure has on the polypeptide are unsatisfactory because of the limitations in the art of rational protein design.” Id. at 16. Appellant argues that “the specific [claimed] method for evaluating an effect that a mutation of a polypeptide of known sequence and structure has on the polypeptide . . . provides the requisite specificity Appeal 2020-002488 Application 14/409,419 7 required to transform the claim from one claiming only a result, as in Electric Power Group, to one claiming a way of achieving it, as in McRO.” Id. at 17. Principles of Law A. Section 101 An invention is patent-eligible if it claims a “new and useful process, machine, manufacture, or composition of matter.” 35 U.S.C. § 101. However, the U.S. Supreme Court has long interpreted 35 U.S.C. § 101 to include implicit exceptions: “[l]aws of nature, natural phenomena, and abstract ideas” are not patentable. E.g., Alice Corp. v. CLS Bank Int’l, 573 U.S. 208, 216 (2014). In determining whether a claim falls within an excluded category, we are guided by the Court’s two-part framework, described in Mayo and Alice. Id. at 217–18 (citing Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 75–77 (2012)). In accordance with that framework, we first determine what concept the claim is “directed to.” See Alice, 573 U.S. at 219 (“On their face, the claims before us are drawn to the concept of intermediated settlement, i.e., the use of a third party to mitigate settlement risk.”); see also Bilski v. Kappos, 561 U.S. 593, 611 (2010) (“Claims 1 and 4 in petitioners’ application explain the basic concept of hedging, or protecting against risk.”). Concepts determined to be abstract ideas, and thus patent ineligible, include certain methods of organizing human activity, such as fundamental economic practices (Alice, 573 U.S. at 219–20; Bilski, 561 U.S. at 611); mathematical formulas (Parker v. Flook, 437 U.S. 584, 594–95 (1978)); and Appeal 2020-002488 Application 14/409,419 8 mental processes (Gottschalk v. Benson, 409 U.S. 63, 67 (1972)). Concepts determined to be patent eligible include physical and chemical processes, such as “molding rubber products” (Diamond v. Diehr, 450 U.S. 175, 191 (1981)); “tanning, dyeing, making water-proof cloth, vulcanizing India rubber, smelting ores” (id. at 182 n.7 (quoting Corning v. Burden, 56 U.S. 252, 267–68 (1854))); and manufacturing flour (Benson, 409 U.S. at 69 (citing Cochrane v. Deener, 94 U.S. 780, 785 (1876))). In Diehr, the claim at issue recited a mathematical formula, but the Court held that “a claim drawn to subject matter otherwise statutory does not become nonstatutory simply because it uses a mathematical formula.” Diehr, 450 U.S. at 187; see also id. at 191 (“We view respondents’ claims as nothing more than a process for molding rubber products and not as an attempt to patent a mathematical formula.”). Having said that, the Court also indicated that a claim “seeking patent protection for that formula in the abstract . . . is not accorded the protection of our patent laws, and this principle cannot be circumvented by attempting to limit the use of the formula to a particular technological environment.” Id. (citation omitted) (citing Benson and Flook); see, e.g., id. at 187 (“It is now commonplace that an application of a law of nature or mathematical formula to a known structure or process may well be deserving of patent protection.”). If the claim is “directed to” an abstract idea, we turn to the second step of the Alice and Mayo framework, where “we must examine the elements of the claim to determine whether it contains an ‘inventive concept’ sufficient to ‘transform’ the claimed abstract idea into a patent- eligible application.” Alice, 573 U.S. at 221 (internal quotation marks Appeal 2020-002488 Application 14/409,419 9 omitted). “A claim that recites an abstract idea must include ‘additional features’ to ensure ‘that the [claim] is more than a drafting effort designed to monopolize the [abstract idea].’” Id. (alterations in original) (quoting Mayo, 566 U.S. at 77). “[M]erely requir[ing] generic computer implementation[] fail[s] to transform that abstract idea into a patent-eligible invention.” Id. B. USPTO Section 101 Guidance In January 2019, the U.S. Patent and Trademark Office (USPTO) published revised guidance on the application of § 101. See 2019 Revised Patent Subject Matter Eligibility Guidance, 84 Fed. Reg. 50 (Jan. 7, 2019) (“Revised Guidance”).3 “All USPTO personnel are, as a matter of internal agency management, expected to follow the guidance.” Id. at 51; see also October 2019 Update at 1. Under the Revised Guidance and the October 2019 Update, we first look to whether the claim recites: (1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes) (“Step 2A, Prong One”); and 3 In response to received public comments, the Office issued further guidance on October 17, 2019, clarifying the Revised Guidance. USPTO, October 2019 Update: Subject Matter Eligibility (the “October 2019 Update”) (available at https://www.uspto.gov/sites/default/files/ documents/peg_oct_2019_update.pdf). Appeal 2020-002488 Application 14/409,419 10 (2) additional elements that integrate the judicial exception into a practical application (see MPEP §§ 2106.05(a)–(c), (e)–(h) (9th ed. Rev. 08.2017, Jan. 2018)) (“Step 2A, Prong Two”).4 Revised Guidance, 84 Fed. Reg. at 52–55. Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look, under Step 2B, to whether the claim: (3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or (4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception. Revised Guidance, 84 Fed. Reg. at 52–56. Revised Guidance Step 2A, Prong 1 Following the Revised Guidance, we first consider whether the claims recite a judicial exception. The Revised Guidance identifies three groupings of subject matter included in the abstract idea exception, including “[m]ental processes—concepts performed in the human mind (including an observation, evaluation, judgment, opinion).” 84 Fed. Reg. at 52. 4 This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. See Revised Guidance - Section III(A)(2), 84 Fed. Reg. 54–55. Appeal 2020-002488 Application 14/409,419 11 Claim 1 recites the steps of: (A) obtaining an initial set of three-dimensional coordinates {x1, ..., xN} for the polypeptide, wherein each respective xi in {x1, ..., xN} is a three dimensional coordinate for an atom in the plurality of atoms in said polypeptide; (B) identifying, in silico, a residue of the polypeptide, and replacing the residue with a different residue, thereby defining a sequence of a mutated polypeptide; [and] (C) identifying a region of the polypeptide based upon the identity of the replaced residue of the mutated polypeptide, the region comprising a plurality of residues. We agree with the Examiner that these steps encompass abstract ideas in the category of mental processes. With regard to step (A), the Specification states that “[i]n some embodiments, the initial structural coordinates {x1, ..., xN} 46 for the complex molecule of interest are obtained by x-ray crystallography, nuclear magnetic resonance spectroscopic techniques, or electron microscopy.” Spec. ¶ 52. However, the claim language does not require any of these techniques, and the Specification makes clear that the initial coordinates can also be obtained simply by accessing a database. See id. ¶ 115 (“The example makes use of an antibody Fc structure (PDB Accession ID 1E4K), herein referred to as the wild type structure.”). Observing information existing in a database can practically be performed in the human mind, and is therefore a mental process. Likewise, “identifying” an amino acid in a polypeptide and “replacing” it to “defin[e] a sequence of a mutated polypeptide” (step (B)) can be carried out in the human mind and therefore encompasses a mental process, notwithstanding the recitation of “in silico.” See Revised Guidance, 84 Fed. Reg. 52 n.14 (“If a claim, under its broadest reasonable Appeal 2020-002488 Application 14/409,419 12 interpretation, covers performance in the mind but for the recitation of generic computer components, then it is still in the mental processes category unless the claim cannot practically be performed in the mind.”). The same is true of “identifying a region of the polypeptide based upon the identity of the replaced residue” (step (C)). However, we do not agree with the Examiner that the remaining steps of claim 1 can be “performed in the mind, but for the recitation of the computer system.” Ans. 5. The Examiner has not established that steps (D) through (G)—altering side chain rotamer conformations and thereby deriving mutated polypeptide structures, clustering based on side chain or main chain conformation, grouping the mutated polypeptide structures based on the clustering, and determining free energy estimates or configurational entropies—can practically be performed in the human mind. Nor do we agree with the Examiner that the recited step of “determining a free energy estimate or configurational entropy of a plurality of mutated polypeptide structures” (claim 1) recites a mathematical concept. Ans. 6. While determining a free energy estimate or configurational entropy undoubtedly involves mathematics, “[a] claim does not recite a mathematical concept (i.e., the claim limitations do not fall within the mathematical concept grouping), if it is only based on or involves a mathematical concept.” October 2019 Update at 3. In addition, the Examiner points to the Specification’s paragraph 23 and dependent claim 11 as “indicat[ing] that the determination of the claimed values is a matter of mathematical computation.” Ans. 6. Both the Specification’s paragraph 23 and dependent Appeal 2020-002488 Application 14/409,419 13 claim 11, however, address a probability function (P(ΔE)), not free energy or configurational entropy calculations. In summary, steps (A), (B), and (C) of claim 1 can practically be performed in the human mind, and therefore recite an abstract idea in the category of mental processes. Revised Guidance Step 2A, Prong 2 Although claim 1 recites an abstract idea, it would still be patent- eligible if “the claim as a whole integrates the recited judicial exception into a practical application of the exception.” Revised Guidance, 84 Fed. Reg. at 54. “A claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.” Id. The analysis of whether a claim integrates a judicial exception into a practical application includes “[i]dentifying whether there are any additional elements recited in the claim beyond the judicial exception(s)” and “evaluating those additional elements individually and in combination to determine whether they integrate the exception into a practical application.” Id. at 54–55. One of the exemplary considerations indicating that an additional element may integrate an exception into a practical application is “[a]n additional element [that] reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field.” Id. at 55. Here, claim 1 as a whole integrates the recited abstract idea (mental processes) into a practical application. As discussed above, in addition to the steps ((A), (B), and (C)) that can practically be performed in the human Appeal 2020-002488 Application 14/409,419 14 mind, claim 1 recites steps (D) through (G): “altering a side-chain rotamer conformation . . . ,” “generating a plurality of sets of clusters . . . ,” “grouping respective mutated polypeptide structures . . . ,” and “determining a free energy estimate or configurational entropy . . . .” Claim 1. Appellant’s Specification states that “[p]rotein engineering frequently involves investigating the properties of a known wild-type sequence, making mutations in a protein of known sequence and structure, and evaluating the effects of these mutations on properties such as protein fold stability, or protein binding.” Spec. ¶ 4. For example, to optimize the binding coefficient, antigen specificity, or thermostability of an antibody, “a protein engineer may study the thermodynamically relevant structural configurations of the residues of the wild-type antibody, and on the basis of these results, elect to mutate one or more residues of the antibody thereby causing the protein sequence to change.” Id. ¶ 5. “[K]nowledge of the ensemble of thermodynamically relevant protein structures for a given primary sequence facilitates the identification of those substitutions that will lead to a protein having more desirable physical characteristics.” Id. ¶ 3. The Specification discusses two known, general approaches to determining thermodynamically relevant structures, one of which “is limited because low free energy states distinct from the ground state are common, and can profoundly affect polymer behavior” and the other of which produces thermodynamic averages that “are often inaccurate, and the sheer size of the generated ensembles make detailed structural analysis challenging.” Id. ¶¶ 6, 7. The Specification also reviews several published approaches, and their limitations. Id. ¶¶ 8–13. Appeal 2020-002488 Application 14/409,419 15 The Specification states that the disclosed “methods for identifying the thermodynamically relevant configurations of a polymer or polymer region . . . combine configurational sampling and structural clustering algorithms in novel ways to identify sets of polymer configurations that are mutually distinct, and have free energies close to the thermodynamic ground state.” Id. ¶ 15. The Specification states that the disclosed methods “are capable of analyzing both residue side chain and residue backbone structural variability, and doing so in a coupled fashion when desired.” Id. Thus, the Specification describes the disclosed, and claimed, method as improving on known methods of modeling the effect of mutations on the structure and thermodynamic stability of a protein. The Specification states that such modeling is useful in protein engineering in order to determine which mutations are likely to have a desired effect on a protein’s properties; e.g., the binding coefficient, antigen specificity, or thermostability of an antibody. We therefore agree with Appellant that the claimed method represents “an improvement to a technical field or technical fields, namely protein engineering” and “rational protein design and modeling.” Appeal Br. 14. Thus, the claimed method, as a whole, is not “directed to . . . [a] patent- ineligible concept.” Alice, 573 U.S. at 217. The same analysis applies to independent claims 44 and 45. See id. at 226 (holding that claims to a computer system and computer-readable medium were not meaningfully distinguished from claims to a method). The Examiner reasons that [t]here are no positive process limitations recited in the claim for actually using the information produced by the abstract idea Appeal 2020-002488 Application 14/409,419 16 outside of the computer (e.g. a real-world practical application or solution to a problem). The claimed method does not require anything more than generating information about in silico coordinates of a molecule that satisfy certain criteria. Ans. 6–7. We do not agree that a physical step, such as actually making a mutant protein, is required in order for the claimed method to constitute a practical application of the recited mental processes. See, e.g., McRO, Inc. v. Bandai Namco Games Amer., Inc., 837 F.3d 1299, 1315 (Fed. Cir. 2016) (“The claimed process uses a combined order of specific rules that renders information into a specific format that is then used and applied to create desired results. . . . While the result may not be tangible, there is nothing that requires a method ‘be tied to a machine or transform an article’ to be patentable.”). As discussed above, the Specification states that, in order to optimize the physical properties of a protein, protein engineers first determine the likely effect of different mutations on the structure and thermodynamic properties of the protein, using methods such as the one defined by claim 1. See Spec. ¶¶ 3–5. The Specification states that different approaches to this problem have been developed, and several approaches have been published in technical journals. Id. ¶¶ 6–13. Thus, the evidence shows that those skilled in the art recognize the practical value of modeling the effect of a mutation on a protein, even if the “real world” consequence is to rule out— and therefore not make—certain mutant proteins because a mutation is predicted to have an undesirable effect on the resulting protein. In summary, we reverse the rejection of independent claims 1, 44, and 45 under 35 U.S.C. § 101. Claims 4, 5, 7, 9–15, 18, 19, 22, 23, 27–30, 36, Appeal 2020-002488 Application 14/409,419 17 38, 40, and 41 depend from claim 1 and we therefore reverse the rejection of these claims as well, for the reasons discussed above. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 4, 5, 7, 9–15, 18, 19, 22, 23, 27–30, 36, 38, 40, 41, 44, 45 101 Eligibility 1, 4, 5, 7, 9–15, 18, 19, 22, 23, 27–30, 36, 38, 40, 41, 44, 45 REVERSED Copy with citationCopy as parenthetical citation