DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 1-20 are pending.
Election/Restrictions
3. Applicant's election with traverse of Group I, claims 1-4, in the reply filed on 05/27/2026 is acknowledged. The traversal is on the ground(s) that the prior art does not disclose the hydantoinase polypeptide engineered to include an I, T, S, or A amino acid substitution at position 64. This is not found persuasive in view of the rejections set forth below. Furthermore, the United States Patent and Trademark Office is not bound by the lack of unity determination by another ISA. 37 C.F.R. 1.484 states the international preliminary examination is a non-binding opinion. Additionally, 37 C.F.R. 1.499 states that, if the Examiner finds that a national stage application lacks unity of invention under 37 C.F.R. 1.475, the Examiner may in an Office action require the applicant in the response to that action to elect the invention to which the claims shall be restricted. Thus, the determination of lack of unity is proper under the PCT treaty.
The requirement is still deemed proper and is therefore made FINAL.
4. Claims 5-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 05/27/2026.
Claims 1-4 are pending and examined on the merits.
Priority
5. Acknowledgement is made of applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) to China Patent Application No. CN202111381310.9, filing date 11/21/2021. The certified copy has been filed in the present application, filed on 05/20/2024.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d), a certified English translation of the foreign application must be submitted. See 37 CFR 41.154(b).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
6. The IDSs filed on 05/20/2024 and 03/03/2026 have been considered by the examiner and copies of the Form PTO/SB/08 are attached to the office action.
Drawings
7. The Drawings filed on 05/20/2024 are acknowledged and accepted by the examiner.
Claim Rejections - 35 USC § 112(b)
8. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
9. Claims 1-4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-4, the recitation “said polypeptide comprises an X64 substitution and at least 90% sequence identity to reference sequence SEQ ID NO: 2” is indefinite because it is unclear whether the X64 substitution corresponds to SEQ ID NO: 2 or to another sequence. Furthermore, the recitation of “at least 90% sequence identity to reference sequence SEQ ID NO: 2” is indefinite because without a definite article with respect to the sequence, it is unclear if the reference sequence is the entire sequence of SEQ ID NO: 2 or fragments of SEQ ID NO: 2. As such, the metes and bounds of the claim cannot be ascertained. It is suggested that applicants clarify the meaning of the claims.
Further regarding claim 2, the term "about" is a relative term which renders the claim indefinite. The term "about" is a term of degree and the examiner has reviewed the specification and can find no examples or teachings that can be used for ascertaining the variance intended by the recited term of degree. Moreover, there is nothing in the specification or prior art of record to indicate that one of ordinary skill in the art could have ascertain the scope of the recited degree. It is suggested that applicant clarify the meaning of the claims. See Supplementary Examination Guidelines for Determining Compliance with 35 U.S.C. §112 and for Treatment of Related Issues in Patent Applications, 76 FR 7162 (Feb. 9, 2011), page 7165.
Claim Rejections - 35 USC § 112
10. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
A. Written Description
11. Claims 1-4 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.2.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
MPEP § 2163 further states that “[s]atisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’"
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
Claims 1-4 are drawn to an engineered hydantoinase polypeptide that catalyzes the asymmetric hydrolysis of 3-isobutylglutarimide to generate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with an enatiomeric excess (ee) value of at least 97% wherein said polypeptide comprises an X64 substitution and at least 90% sequence identity to reference sequence SEQ ID NO: 2, wherein the amino acid residue at residue position X64 is selected from the group consisting of I, T, S, and A. In view of the indefiniteness of the claims, the claim is interpreted as encompassing any fragments of the claimed sequence, and as such the structure of the polypeptide is unlimited.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus of “engineered hydantoinase polypeptide that catalyzes the asymmetric hydrolysis of 3-isobutylglutarimide to generate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with an enatiomeric excess (ee) value of at least 97%” as encompassed by the claims (i.e. an engineered hydantoinase polypeptide comprising the amino acid sequence of SEQ ID NO: 2 with the exception of a substitution at positions corresponding to positions 8, 39, 46, 51, 62, 63, 64, 66, 67, 71, 73, 95, 97, 113, 152, 159, 189, 199, 201, 215, 254, 255, 257, 263, 264, 265, 266, 267, 288, 292, 320, 329, 336, 337, 340, 462, 467, 474, 476, and 479 of the amino acid sequence of SEQ ID NO: 2). Other than the above disclosed species there is no other drawings or structural formulas of the infinite polypeptides of any function as encompassed by the claims. As stated above, the breadth of the claims is interpreted as encompassing any fragments of the claimed sequence, and as such the structure of the polypeptide is unlimited.
Regarding the level of skill and knowledge in the art of amino acid modification, MPEP 2144.08.II.A.4.(c) states, "[i]n the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution ("the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein." Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990)."
The reference of Singh et al. (Current Protein and Peptide Science, 2017; examiner cited) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes [see p. 7, column 1, top].
The reference of Zhang et al. (Structure, 2018; examiner cited) discloses that a mutation of a residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide [p. 1475, column 1].
In the Federal Circuit decision, Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337 (Fed. Cir. 2021), the courts found that for broad claims to a nucleic acid encoding a chimeric T cell receptor with a functional requirement to bind a target, “the written description must demonstrate that the applicant made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus”. In the instant case, the claims are drawn to polypeptide of unlimited structure, and the specification does not disclose sufficient structural features in the claimed polypeptide sequence associated with the desired activity to allow an ordinary artisan to distinguish which multiple mutated sequences will result in engineered hydantoinase polypeptide that catalyzes the asymmetric hydrolysis of 3-isobutylglutarimide to generate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with an enatiomeric excess (ee) value of at least 97%. While a person skilled in the art might be able to embark on their own research program to find suitable multiply modified polypeptides, the four corners of the written description do not demonstrate possession of such. This analysis is consistent with AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014) which required an inventor to show “that one has truly invented the genus, i.e. that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus”.
Given that the specification discloses only a relative few representative species of the claimed genus, and there is a very high level of unpredictability in the art of amino acid modification, the specification is considered to be insufficient to describe the claimed genus of polypeptides. In this case, the specification at best describes a research plan for making, testing, and identifying those species that are encompassed by the claimed genus of polypeptides, however, a plan for making the claimed invention is not sufficient to show possession at the time of filing. One of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus, and thus, that the applicant was not in possession of the recited genus.
For these reasons, it is the examiner’s position that the specification fails to adequately describe the claimed invention.
B. Scope of Enablement
12. Claims 1-4 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while enabling for an engineered hydantoinase polypeptide comprising the amino acid sequence of SEQ ID NO: 2 with the exception of a substitution at positions corresponding to positions 8, 39, 46, 51, 62, 63, 64, 66, 67, 71, 73, 95, 97, 113, 152, 159, 189, 199, 201, 215, 254, 255, 257, 263, 264, 265, 266, 267, 288, 292, 320, 329, 336, 337, 340, 462, 467, 474, 476, and 479 of the amino acid sequence of SEQ ID NO: 2 catalyzing the asymmetric hydrolysis of 3-isobutylglutarimide to generate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with an enatiomeric excess (ee) value of at least 97%, does not reasonably provide enablement for all engineered hydantoinase polypeptides as encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
“The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue.” In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976). Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) as follows: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a). The Factors considered to be most relevant to the instant rejection are addressed in detail below.
The breadth of the claims: Claims 1-4 are drawn to an engineered hydantoinase polypeptide that catalyzes the asymmetric hydrolysis of 3-isobutylglutarimide to generate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with an enatiomeric excess (ee) value of at least 97% wherein said polypeptide comprises an X64 substitution and at least 90% sequence identity to reference sequence SEQ ID NO: 2, wherein the amino acid residue at residue position X64 is selected from the group consisting of I, T, S, and A. In view of the indefiniteness of the claims, the claim is interpreted as encompassing any fragments of the claimed sequence, and as such the structure of the polypeptide is unlimited.
The state of the prior art; The level of one of ordinary skill; and The level of predictability in the art: As noted above, the structure of the claimed engineered hydantoinase is unlimited.
Regarding the level of skill and knowledge in the art of amino acid modification, MPEP 2144.08.II.A.4.(c) states, "[i]n the area of biotechnology, an exemplified species may differ from a claimed species by a conservative substitution ("the replacement in a protein of one amino acid by another, chemically similar, amino acid... [which] is generally expected to lead to either no change or only a small change in the properties of the protein." Dictionary of Biochemistry and Molecular Biology 97 (John Wiley & Sons, 2d ed. 1989)). The effect of a conservative substitution on protein function depends on the nature of the substitution and its location in the chain. Although at some locations a conservative substitution may be benign, in some proteins only one amino acid is allowed at a given position. For example, the gain or loss of even one methyl group can destabilize the structure if close packing is required in the interior of domains. James Darnell et al., Molecular Cell Biology 51 (2d ed. 1990)."
The reference of Singh et al. (Current Protein and Peptide Science, 2017; examiner cited) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes [see p. 7, column 1, top].
The reference of Zhang et al. (Structure, 2018; examiner cited) discloses that a mutation of a residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide [p. 1475, column 1].
The evidence of record demonstrates that identifying which of the infinite members of the polypeptide genus capable of catalyzing the asymmetric hydrolysis of 3-isobutylglutarimide to generate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with an enatiomeric excess (ee) value of at least 97% was not known in the art, and one of skill in the art would recognize a high level of unpredictability in the art of amino acid modification.
The amount of direction provided by the inventor and The existence of working examples: The specification discloses the following working examples of engineered hydantoinase polypeptide that catalyzes the asymmetric hydrolysis of 3-isobutylglutarimide to generate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with an enatiomeric excess (ee) value of at least 97%, i.e. an engineered hydantoinase polypeptide comprising the amino acid sequence of SEQ ID NO: 2 with the exception of a substitution at positions corresponding to positions 8, 39, 46, 51, 62, 63, 64, 66, 67, 71, 73, 95, 97, 113, 152, 159, 189, 199, 201, 215, 254, 255, 257, 263, 264, 265, 266, 267, 288, 292, 320, 329, 336, 337, 340, 462, 467, 474, 476, and 479 of the amino acid sequence of SEQ ID NO: 2. Other than these working examples, the specification fails to disclose any other working examples of engineered hydantoinase polypeptides as encompassed by the claims.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: In the Federal Circuit decision of Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 1156 (Fed. Cir. 2019), the court stated that “the key enablement question is whether a person of ordinary skill in the art would know, without undue experimentation, which [species] would be effective….because of the many thousands of [species] which need to be screened for…efficacy, the quantity of experimentation needed is large and weighs in favor of non-enablement.” In the instant case, the number is higher than the thousands, and as such, the quantity of experimentation would be orders of magnitude more than that in Idenix.
While methods for modifying the amino acid sequence of a polypeptide were known before the effective filing date, it was not routine in the art to screen by a trial and error process for all engineered hydantoinases with respect to a reference polypeptide comprising SEQ ID NO: 2 as broadly encompassed by the claims.
In view of the overly broad scope of the claims, the lack of guidance and working examples provided in the specification, the high level of unpredictability, and the state of the prior art, undue experimentation would be necessary for a skilled artisan to make and use the entire scope of the claimed invention. Applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Conclusion
13. Status of the claims:
Claims 1-20 are pending.
Claims 5-20 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 1-4 are rejected.
No claims are in condition for an allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
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