DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-17, 22 in the reply filed on 05/18/2026 is acknowledged. Election of species of SEQ ID NOs: 30-31, 33, 35 is acknowledged.
Claims 2, 4, 6-8, 23, 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/18/2026.
Information Disclosure Statement
The information disclosure statement filed 10/02/2023 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered.
Claim Rejections - 35 USC § 112
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.
Claims 1, 3, 5, 11-17, 22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for promoting production of gamma-globin in cells by administering cytidine deaminase, does not reasonably provide enablement for promoting production of gamma-globin in cells by administering any other nucleobase deaminase. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The claimed invention is not supported by an enabling disclosure taking into account the Wands factors. In re Wands, 858/F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988). In re Wands lists a number of factors for determining whether or not undue experimentation would be required by one skilled in the art to make and/or use the invention. These factors are: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples of the invention, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, and the breadth of the claim.
Claims are broadly drawn to methods for promoting production of gamma-globin in cells by administering Cas protein, nucleobase deaminase and specific gRNAs.
Instant methods encompass administering any nucleobase deaminase for promoting production of gamma-globin in cells.
Instant specification, though, teaches administration of only cytidine deaminase for promoting production of gamma-globin in cells with specific gRNAs as claimed (see Examples 1 and 2). Cytidine deaminase promotes C to U changes in genome (see paragraph [0108]). Any other deaminase promotes changes of different nucleotides and it is not clear from specification if such different changes are beneficial for promoting production of gamma-globin in cells or not. Further, Example 3 of specification discusses cytidine deaminase-specific inhibitor. There is no discussion of inhibitors of any other possible deaminases.
Prior art teaches use of nucleobase deaminases for gene editing. For example, Mali et al (WO 2020/051555, March 2020) teaches use of adenosine deaminase or cytidine deaminase for base editing (see paragraphs [0112, 0124]), but not in the context of increasing gamma-globin production.
Instant specification fails to provide guidance on using any other nucleobase deaminase for gamma-globin production except for cytidine deaminase.
The guidance provided in the specification relates to administration of only one nucleobase deaminase, which affects only one specific nucleotide (cytidine), and fails to address the issue of administration of any other deaminase, which would affect different type of nucleotide.
In the absence of guidance, undue trial and error experimentation would have been required by one skilled in the art at the time invention was made to use any other nucleobase deaminase than cytidine deaminase for increasing production of gamma-globin in cells as instantly claimed. Given the breadth of the claims, unpredictability of the art and lack of guidance of the specification, as discussed above, undue experimentation would be required by one skilled in the art to make and use the claimed invention commensurate in scope with the claims.
Claims 1, 3, 5, 9-17 and 22 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.
Claims are broadly drawn to methods for promoting production of gamma-globin in cells by administering Cas protein, nucleobase deaminase, specific gRNAs and nucleobase deaminase inhibitor.
Claims encompass a wide genus of nucleobase deaminase inhibitors of various nature and structure.
Instant specification teaches that nucleobase deaminase inhibitors can be inhibitory domains of nucleobase deaminase, specifically cytidine deaminase (see paragraph [0013]) and provides examples of such specific inhibitors in Tables B, B1-B3. Specification teaches that such inhibitor inhibits activity of nucleobase deaminase until the whole base editing complex is assembled at target genomic site (see paragraph [0070]). Example 3 of specification identifies the most effective inhibitor out of several disclosed.
Prior art teaches a variety of possible nucleobase deaminase inhibitors. For example, Ferraris et al (Journal of Medicinal Chemistry, 2014, 57: 2582-2588) teach small molecule inhibitors of cytidine deaminase (see Abstract). It is not clear if such inhibitor can be used in instant methods, because all teachings of instant disclosure relate to specific protein-based inhibitors.
Specification does not describe structure for representative species of Applicant's broadly claimed genus. Thus, their function for effective production of gamma-globin is either unknown or unpredictable.
The genus of nucleobase deaminase inhibitors encompasses a large number of unknown structures and one of skilled in the art cannot reliably predict which member of the genus would successfully increase production of gamma-globin, and which will not.
There is no description of the necessary and sufficient elements of the species encompassed by the breadth of the claims.
The only species described in specification are cytidine deaminase protein-based inhibitors.
Applicant fails to describe representative members of Applicant's broadly claimed genus.
One of the skill in the art would not recognize that Applicant was in possession of the necessary common attributes or features of the genus in view of the disclosed species. Since the disclosure fails to describe the common attributes that identify members of the genus, and because the genus is highly variant, cytidine deaminase inhibitors shown in Tables B, B1-B3 are not sufficient to describe the claimed genus. Therefore, given the lack of written description in the specification with regard to the structural and functional characteristics of the claimed compositions, it is not clear that Applicant was in possession of the claimed genus at the time this application was filed.
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.
Claims 1, 3, 5, 9-17, 22 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.
Claim 1 recites the term “preferably” in the last line. It is not clear if the limitations following the term are required as part of the claim or not.
Claims 3, 5, 9-17 and 22 are rejected based on their dependency on claim 1.
Claim 15 recites the limitation "the protease cleavage site" in the last line. There is insufficient antecedent basis for this limitation in the claim. For purpose of examination it will be considered that claim 15 depends on claim 11, but appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3, 5, 9-10, 17, 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gori et al (WO 2017/160890, September 2017) and in further view of Evans et al (WO 2020/051562, March 2020) and Boitano et al (WO 2017/115268, July 2017, cited from IDS).
Gori teach methods for increasing expression of gamma-globin genes by administering CRISPR/Cas-mediated genome editing system (see middle paragraph on page 5), such system including gRNAs of SEQ ID NOs: 251-901 (see middle paragraph on page 6), wherein one or more gRNAs can be delivered (see last paragraph on page 27). Such gRNAs can be single guide RNAs, sgRNAs (see last paragraph on page 34). Guide RNA of SEQ ID NO: 333 is 100% identical to instant SEQ ID NO: 30 (see Table 8 on page 158). Another gRNA, of SEQ ID NO: 289 is 17 nucleotides long with nucleotides 7-16 identical to instant SEQ ID NO: 31 and nucleotides 1-10 identical to instant SEQ ID NO: 33 (see sequence listing). Cas9 protein and gRNAs can be delivered encoded in polynucleotide (see middle paragraph on page 105). Cas9 protein can be Streptococcus pyogenes Cas9, SpCas9 (see bridging paragraph between pages 156-157). The patient to treat can be suffering from β-thalassemia (see middle paragraph on page 1).
Gori do not teach administration in combination with cytidine deaminase, or gRNAs further comprising gRNA of SEQ ID NO: 2 and SEQ ID NO: 12.
Evans teach improvement of CRISPR/Cas9 gene editing system by further including cytidine deaminase in such system (see Abstract) such as APOBEC3B or APOCEB3C (see lines 1-10 on page 43). Such more precise base editing improves efficiency by reducing number of insertions or deletions (see lines 20-25 on page 127).
Boitano teach methods of treatment of β-thalassemia by administering CRISPR/Cas9 and one or more gRNAs (see lines 19-27 on page 1). One of such gRNAs comprises SEQ ID NO: 2038 (see last line in Table 14 on page 359), 100% identical to instant SEQ ID NO: 2, and another one is of SEQ ID NO: 1439 (see Table 2 on page 134), with nucleotides 6-25 100% identical to instant SEQ ID NO: 12.
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to improve method of Gori by including cytidine deaminase as taught by Evans or use gRNAs taught by Boitano et al, arriving at instant invention. One of the ordinary skill in the art would be motivated to do so, because Evans teach improvement of CRISPR/Cas9 gene editing methods such as taught by Gori by further including cytidine deaminase to improve efficiency. Further, Boitano suggest different gRNAs for treatment of the same disease as Gori, making it obvious to use those in methods of Gori.
Claim(s) 1, 9-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gori, above, and in further view of Chen et al (WO 2020/156575, August 2020, cited from IDS).
Teachings of Gori are discussed above.
Gori do not teach administration of cytidine deaminase inhibitor fused via protease cleavage site, such inhibitor being inhibitory domain of cytidine deaminase comprising instant SEQ ID NO: 191 and protease is TuMV protease.
Chen teach integration of CRISPR/Cas9 gene editing system with cytidine deaminases such as APOBEC3B (see paragraphs [0004, 0009]) and further improving the system to include nucleobase deaminase inhibitors to reduce off-target effects (see paragraph [0006]). Such inhibitor can be cytidine deaminase inhibitory domain of SEQ ID NO: 1 (see paragraph [0010]), which is 100% identical to instant SEQ ID NO: 191. The inhibitor can be fused to cytidine deaminase through protease cleavage site (see paragraph [0007]), such protease cleavage site can be of TuVM protease (see paragraph [0012]).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to improve method of Gori by further including cytidine deaminase with fused cytidine deaminase inhibitory domain as taught by Chen, arriving at instant invention. One of the ordinary skill in the art would be motivated to do so to reduce off-target effects as taught by Chen.
Double Patenting
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.
Claims 1, 3, 5, 9-17, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,384,353 in view of Gori and Evans, above. Claims from ‘353 teach methods for nucleic acid editing comprising administering a cytidine deaminase, cleavably fused to a second fragment comprising an inhibitor to the cytidine deaminase, wherein said inhibitor is an inhibitor domain from a cytidine deaminase, and wherein the editing is conducted with a protease such as TuMV that cleaves the second fragment from the first fragment thereby activating the nucleobase deaminase. Teachings of Gori and Evans are discussed above. It would have been obvious to one of the ordinary skill in the art to apply method from ‘353 to methods of increasing expression of gamma-globin taught by Gori based on teachings of Evans, arriving at instant invention.
Claims 1, 3, 5, 9-17, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,840,685 in view of Gori and Evans, above. Claims from ‘685 teach methods for nucleic acid editing comprising administering two guide RNAs and nucleobase deaminase, cleavably fused to a second fragment comprising an inhibitor to the nucleobase deaminase, wherein said inhibitor is an inhibitor domain from a cytidine deaminase, and wherein the editing is conducted with a protease that cleaves the second fragment from the first fragment thereby activating the nucleobase deaminase. Teachings of Gori and Evans are discussed above. It would have been obvious to one of the ordinary skill in the art to apply method from ‘685 to methods of increasing expression of gamma-globin taught by Gori based on teachings of Evans, arriving at instant invention.
Claims 1, 3, 5, 9, 17, 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,884,947 in view of Gori and Evans, above. Claims from ‘947 teach fusion protein of cytidine deaminase and Cas9. Teachings of Gori and Evans are discussed above. It would have been obvious to one of the ordinary skill in the art to use fusion protein from ‘947 in methods of increasing expression of gamma-globin taught by Gori based on teachings of Evans, arriving at instant invention.
Claims 1, 3, 5, 9, 17, 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 11 of copending Application No. 18/277,768 in view of Gori and Evans, above. Claim from ‘768 teach fusion protein of nucleobase deaminase and Cas9. Teachings of Gori and Evans are discussed above. It would have been obvious to one of the ordinary skill in the art to use fusion protein from ‘768 in methods of increasing expression of gamma-globin taught by Gori based on teachings of Evans, arriving at instant invention.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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