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, 6, 8, 13-14, 17, 19, 22-23, 26, 40, 42-43, 52, 57, 75, 78, 88, 91, and 93 are pending.
Election/Restrictions
3. Applicant’s election without traverse of Group I and the species SEQ ID NO: 50, 200, and 299 in the reply filed on 03/06/2026 is acknowledged.
4. Claims 26, 40, 42-43, 52, 57, 75, 91, and 93 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/06/2026.
Claims 1, 6, 8, 13-14, 17, 19, 22-23, 78, and 88 will be examined to the extent that they read on the elected species SEQ ID NO: 50, 200, and 299.
Priority
5. Acknowledgement is made of applicants’ claimed domestic priority to U.S. Provisional Application No. 63/314598, filed on 02/28/2022.
Information Disclosure Statement
6. The IDSs filed on 06/12/2023, 06/27/2023, 07/26/2024, 09/11/2024, and 03/06/2026 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 02/28/2023 are acknowledged and accepted.
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, 6, 8, 13-14, 17, 19, 22-23, 78, and 88 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, 6, 8, 13-14, 17, 19, 22-23, 78 and 88, the recitation of “a portion” as it relates to a polypeptide is indefinite because it is unclear what the term portion is intended to encompass with respect to structure. As such, the metes and bounds upon which patent protection is sought cannot be ascertained from the claims.
Regarding claim 22, that recitation of “having about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the amino acid sequence of a wild-type CRISPR-Cas effector protein” is indefinite without a structure or sequence to compare it is unclear what wild-type CRISPR-Cas effector the claim is referring to. The metes and bounds upon which patent protection is sought cannot be ascertained from the claims.
Claim Rejections - 35 USC § 112(a)
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
12. Claims 1, 6, 8, 13-14, 17, 19, 22-23, 78, and 88 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.
Claims 1, 6, 8, 13-14, 17, 19, and 88 are drawn in relevant part to an engineered protein and a complex comprising: a first polypeptide that is a Type V CRISPR-Cas effector polypeptide and is devoid of a nuclease domain; and a second polypeptide that is all or a portion of one or more of SEQ ID NO: 200. The structure and function of the engineered protein is unlimited. Further in view of the indefinite term “portion”, the structure and function of the second polypeptide is unlimited.
Claim 22 is drawn in relevant part to the engineered protein of claim 1, wherein the engineered protein comprises an amino acid sequence having about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the amino acid sequence of a wild-type CRISPR-Cas effector protein.
Claim 23 is drawn in relevant part to the engineered protein of claim 1, wherein the first polypeptide is a portion of one or more of SEQ ID NO: 50, and wherein the engineered protein further comprises a third polypeptide that is a different portion of one or more of SEQ ID NO: 50. In view of the indefinite term “portion”, the structure and function of the polypeptide is unlimited.
Claim 78 is drawn in relevant part to an engineered protein comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 299.
In this case, the specification discloses an actual reduction to practice of the following representative species of the genus of “engineered proteins” as encompassed by the claims (i.e. a first portion comprising the amino acid sequence of SEQ ID NO: 241, 243, 245, 247, 249, 251, and 253, a second portion comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and third portion comprising the amino acid sequence of SEQ ID NO: 50-66, 151, 238 and 326 fused to a deaminase having deaminase activity). Other than the above disclosed species there is no other drawings or structural formulas disclosed of the infinite number of engineered proteins comprising a first portion of a Type V CRISPR-Cas effector protein devoid of a nuclease domain, a second portion and a third portion as encompassed by the claims.
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].
There is no prior-art or disclosed teaching regarding the structure of the infinite structure of the portion of a polypeptide having any function, and there is no disclosed or art recognized correlation between any structure other than a first portion comprising the amino acid sequence of SEQ ID NO: 241, 243, 245, 247, 249, 251, and 253, a second portion comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and third portion comprising the amino acid sequence of SEQ ID NO: 50-66, 151, 238 and 326 fused to a deaminase having deaminase activity. Given what is known in the art about the likely outcome of substitutions on structure, conservation of structure is not necessarily a surrogate for conservation of function. In this case, there is no disclosed correlation between structure and function. Accordingly, one of skill in the art would not accept the disclosure a first portion comprising the amino acid sequence of SEQ ID NO: 241, 243, 245, 247, 249, 251, and 253, a second portion comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and third portion comprising the amino acid sequence of SEQ ID NO: 50-66, 151, 238 and 326 fused to a deaminase having deaminase activity as being representative of all engineered proteins of any activity as encompassed by the claims. As such, the specification, taken with the pre-existing knowledge in the art of amino acid substitution, fails to satisfy the written description requirement of 35 U.S.C. 112(a).
B. Scope of Enablement
13. Claims 1, 6, 8, 13-14, 17, 19, 22-23, 78, and 88 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 protein comprising a first portion comprising the amino acid sequence of SEQ ID NO: 241, 243, 245, 247, 249, 251, and 253, a second portion comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and third portion comprising the amino acid sequence of SEQ ID NO: 50-66, 151, 238 and 326 fused to a deaminase having deaminase activity does not reasonably provide enablement for all engineered proteins 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.
(A) The breadth of the claims: Claims 1, 6, 8, 13-14, 17, 19, and 88 are drawn in relevant part to an engineered protein and a complex comprising: a first polypeptide that is a Type V CRISPR-Cas effector polypeptide and is devoid of a nuclease domain; and a second polypeptide that is all or a portion of one or more of SEQ ID NO: 200. The structure and function of the engineered protein is unlimited. Further in view of the indefinite term “portion”, the structure and function of the second polypeptide is unlimited.
Claim 22 is drawn in relevant part to the engineered protein of claim 1, wherein the engineered protein comprises an amino acid sequence having about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the amino acid sequence of a wild-type CRISPR-Cas effector protein.
Claim 23 is drawn in relevant part to the engineered protein of claim 1, wherein the first polypeptide is a portion of one or more of SEQ ID NO: 50, and wherein the engineered protein further comprises a third polypeptide that is a different portion of one or more of SEQ ID NO: 50. In view of the indefinite term “portion”, the structure and function of the polypeptide is unlimited.
Claim 78 is drawn in relevant part to an engineered protein comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 299.
C) The state of the prior art; (D) The level of one of ordinary skill; and (E) The level of predictability in the art: As noted above, the structure and function of the claimed engineered protein comprising a first polypeptide and a second polypeptide is unlimited.
It is well-known in the prior art that the amino acid sequence of a polypeptide determines the polypeptide’s functional properties. The positions within a protein's sequence where modifications can be made with a reasonable expectation of success in obtaining a polypeptide having the desired activity/utility are limited in any protein and the result of such modifications is highly unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g., multiple substitutions.
It is well-known in the art that even a single amino acid alteration can alter the folding of a polypeptide. See, e.g., MPEP 2144.08.II.A.4.(c), which 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].
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The specification discloses the following working examples of engineered protein comprising a first polypeptide that is a Type V CRISPR-Cas effector polypeptide and is devoid of a nuclease domain; and a second polypeptide that is all or a portion of one or more of SEQ ID NO: 200, i.e. an engineered protein comprising a the amino acid sequence of SEQ ID NO: 241, 243, 245, 247, 249, 251, and 253, a second portion comprising the amino acid sequence of 190, 192, 196, 199, 208-235 and 291-293, and third portion comprising the amino acid sequence of SEQ ID NO: 50-66, 151, 238 and 326 fused to a deaminase having deaminase activity.
Other than these working examples, the specification fails to disclose any other working examples of engineered proteins of any function. Moreover, the specification fails to provide guidance regarding what additional modifications to said engineered protein that result in any activity.
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).
Double Patenting
14. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
15. Claims 1, 6, 8, 13-14, 17, 19, 22-23, 78, and 88 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 7, 11-14, 16-17, 22-23, 47-53, and 75-79 of copending Application No. 17/459166. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1, 4-5, 7, 11-14, 16-17, 22-23, 47-53, and 75-79 of the ‘166 application recite an engineered Cas effector protein comprising a first CRISPR-Cas effector polypeptide that is a first portion of a first Cas12a protein, wherein the first CRISPR-Cas effector polypeptide is devoid of a nuclease domain; a second CRISPR-Cas effector polypeptide that is a second portion of a second Cas12a protein, wherein the first CRISPR-Cas effector polypeptide is different than the second CRISPR-Cas effector polypeptide; and a heterologous polypeptide that is heterologous to the first Cas12a protein and to the second Cas12a protein, wherein the heterologous polypeptide comprises a first nuclease domain and the heterologous polypeptide is between the first CRISPR-Cas effector polypeptide and the second CRISPR-Cas effector polypeptide, and wherein the heterologous polypeptide when the engineered Cas effector protein is optimally aligned to SEQ ID NO: 50, is between two amino acids selected from amino acid residues 270-350 of SEQ ID NO : 50. The dependent claims further limit the heterologous nuclease domain to an HNH domain.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Citation of Pertinent Prior Art
16. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Zhang F et al. (WO2019/126762 A2 with US Patent Application Publication 2021/0079366 cited as certified copy due to file size of the WIPO document; examiner cited) teach engineered CRISPR Cas effector proteins; however, does not disclose a first polypeptide that is a Type V CRISPR-Cas effector polypeptide that is devoid of a nuclease domain.
Conclusion
17. Status of the claims:
Claims 1, 6, 8, 13-14, 17, 19, 22-23, 26, 40, 42-43, 52, 57, 75, 78, 88, 91, and 93 are pending.
Claims 26, 40, 42-43, 52, 57, 75, 91, and 93 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 1, 6, 8, 13-14, 17, 19, 22-23, 78, and 88 are rejected.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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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