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/Restriction
Applicant’s election without traverse of Group 1, claims 1-7 and 9-20 in the reply filed on 08 December 2025 was acknowledged.
Claim 26 was withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 08 December 2025.
Claim Status
Claims 1, 5-7, and 9-20 are currently amended, claims 8, 21-25, and 27-30 were previously cancelled, claims 2-4 are newly canceled, claim 26 is withdrawn, and claims 1, 5-7 and 9-20 have been considered on their merits.
Withdrawn Rejections
The claim rejections under 35 USC § 112(b) have been withdrawn due to Applicant’s amendments to the claim.
The claim rejections under 35 USC § 103 have been withdrawn due to Applicant’s amendments to the claim. However, new grounds of rejection have been set forth below.
The provisional non-statutory double patenting rejections have been withdrawn due to Applicant’s amendments to the claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1, 6, and 20 are rejected under 35 U.S.C. 103 as being obvious over Kwiatkowski et al., (WO 2020/053815 A1, published 19 March 2020, of record) in view of Hinderer et al. (WO 2017/024198 A1, published 09 February 2017, IDS ref., of record) and Wilson et al. (US 2022/0389457 A1, priority to provisional application 62/924,970, filed on 23 October 2019, of record).
The Wilson reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claim 1, Kwiatkowski teaches conjugates of a glucagon-like-peptide (GLP), for example, a glucagon-like-peptide 1 (GLP-1) polypeptide or analogs thereof (Abstract). Kwiatkowski teaches SEQ ID NO: 11, Dulaglutide (LY2189265, TRULICITY®), which is a molecule consisting of two identical, disulfide-linked chains, each containing a human GLP-1 analog sequence covalently linked to a modified human immunoglobulin G4 (IgG4) heavy chain fragment (Fc) by a small peptide linker (p. 63 lines 16-19). Kwiatkowski teaches the GLP-1 analog sequence, SEQ ID NO:8, which is identical to instant SEQ ID NO: 3; the IgG4 Fc sequence, SEQ ID NO: 9, which is identical to instant SEQ ID NO: 11; and the small peptide linker, SEQ ID NO: 10, which is identical to instant SEQ ID NO: 13 (pp. 63-64). Kwiatkowski teaches the sequence of one monomer of Dulaglutide, SEQ ID NO: 11, which consists of instant SEQ ID NOs: 3, 10, and 11. See alignment of SEQ ID NO: 11 and instant SEQ ID NO: 14 below:
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Kwiatkowski teaches does not teach a viral vector comprising said sequence or a human thrombin leader sequence prior to the GLP-1 analog.
However, Hinderer teaches viral vectors comprising nucleic acid molecules comprising a sequence encoding a propeptide and the active portion of GLP-1, wherein, when expressed, the N-terminal amino acid of GLP-1 immediately follows the C-terminal amino acid of the propeptide (Abstract). Hinderer teaches this approach could provide a convenient and effective therapy for type II diabetes (T2DM) in both humans and other species affected by the
disease (para. [0003]). Hinderer teaches anticoagulant factor II is also called prothrombin, also known as factor II which is used interchangeably with prothrombin and thrombin (para. [00057]). Hinderer teaches in one embodiment, the propeptide sequence is a factor II leader sequence (para. [00057]). Hinderer teaches the amino acid sequence of human Factor II is known and the propeptide sequence is amino acids 1-43 of SEQ ID NO: 28 (para. [00057]). SEQ ID NO: 28 is identical to instant SEQ ID NO: 7.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the sequence of Dulaglutide of Kwiatkowski with the human propeptide and viral vector of Hinderer with a reasonable expectation of success because Hinderer teaches GLP-1 expression constructs have been developed for use in subjects including companion animals and humans, in which the leader propeptide is derived from proteins endogenous to the species of the veterinary or human patient (para. [00024]). Additionally, viral vectors could provide long-lasting expression of GLP-1 because delivering the fusion peptide via viral vector would enable a patient's own cells to produce the GLP-1 receptor agonist, rather than relying on periodic injections. One would be motivated to utilize the sequence of Dulaglutide of Kwiatkowski with the human propeptide and viral vector of Hinderer because Hinderer teaches GLP-1 cannot be expressed in its native form from a gene therapy vector due to the need for cell-specific proteases to release the active peptide from the precursor polypeptide (para. [0004]). Additionally, Hinderer teaches, in mice, thrombin propeptide produced more active GLP-1 than other propeptide constructs (para. [00099]). While Hinderer focus is directed towards animal studies, the success of the thrombin propeptide would provide motivation to try in human patients and the propeptide is required to be derived from proteins endogenous to the species.
Kwiatkowski in view of Hinderer render obvious SEQ ID NO: 14, thus, also render obvious the at least 75% identical to nucleic acid sequence encoding the fusion protein, SEQ ID NO: 15.
Hinderer teaches an expression cassette comprises a nucleic acid molecule comprising the GLP-1 construct coding sequence, promoter, other regulatory sequences and packaged into the capsid of a viral vector (para. [00064]). Hinderer teaches the expression cassette for generating a viral vector contains the GLP-1 construct sequences flanked by packaging signals of the viral genome and other expression control sequences (para. [00064]). Hinderer teach the minimal sequences required to package the expression cassette into an AAV viral particle are the AAV 5' and 3' ITRs (para. [00068]).
Hinderer teaches the rAAV has a capsid selected from AAV8, AAVrh64Rl, AAV9, AAVhu37 or AAVrh10 (para. [00011]). Kwiatkowski in view of Hinderer do not teach wherein the viral vector is an rAAV having the AAV capsid of AAVrh91.
However, Wilson teaches recombinant AAV (rAAV) comprising an AAV capsid having packaged therein a vector genome, wherein, in certain embodiments the rAAV capsid is AAV9, AAVhu68, or AAVrh91 (para. [0007]). Thus, suggesting these rAAV capsids are suitable alternatives.
Therefore, it would have been obvious to one of ordinary skill in the art to substitute the AAVrh91 capsid of Wilson with the capsid of Hinderer because Wilson and Hinderer both teach AAV9 as an exemplary capsid and Wilson suggests the AAV9 and AAVrh91 capsids are suitable alternatives. One would be motivated to substitute the AAVrh91 capsid of Wilson with the capsid of Hinderer in order to avoid potential hepatotoxicity which AAV9 capsid is known to cause at high doses and to avoid potential pre-existing immunity to AAV9 capsid which would limit efficacy. It has been held that "a person with ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense." See KSR International Co. v Teleflex, Inc. 82 USPQ2d 1385 at 1390.
Additionally, it would have been prima facie obvious to substitute the AAV9 capsid for the AAVrh91 capsid because they were all known as equivalents in the field of adherent cells for biological production systems, and one would have had a reasonable expectation that they would have worked in the same manner. Substitution of one known element for another known element, the elements having equivalent effect, is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See MPEP 2143(I).
Thus, the teachings of Kwiatkowski in view of Hinderer and Wilson render obvious the limitations of claim 1.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Regarding claim 6, Hinderer teaches the ITR sequences are from AAV2 and an
expression cassette for an AAV vector comprises an AAV 5' ITR, the propeptide-GLP-1
active peptide coding sequences and any regulatory sequences, and an AAV 3' ITR (para. [00068]).
Regarding claim 20, the limitation directed to the composition being suitable for use in treating a metabolic disease, is an intended use statement which is not limiting because it does not add structure to the composition. Therefore, the claim reads as an aqueous liquid and the viral vector of claim 1. Kwiatkowski teaches pharmaceutical compositions comprising administration as a solution or a suspension in an aqueous liquid (p. 92, line 18) and Hinderer teaches the rAAV is preferably suspended in a physiologically compatible carrier, to include saline (para. [00079]). Thus, the teachings of Kwiatkowski and Hinderer render obvious the limitations of the claim to include a pharmaceutical composition comprising an aqueous solution and the viral vector of claim 1.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant’s arguments, see page 6 of the Remarks, filed 27 April 2026, with respect to Kwiatkowski nor Hinderer requiring an AAVrh91 capsid have been fully considered and are persuasive. Specifically, due to the amendment to the independent claim to include the AAVrh91 capsid overcomes the previous rejection of Kwiatkowski in view of Hinderer, therefore, rejection under 103 has been withdrawn.
However, upon further consideration, new grounds of rejection are made in view of Kwiatkowski, Hinderer, and Wilson. While this combination of references were used previously to reject claim 4, for example, the rejections have been revised to address the newly amended claims. While Kwiatkowski in view of Hinderer do not teach the AAVrh91 capsid, Wilson suggests AAVrh91 would be a suitable substitute for the AAV9 capsid, as discussed in the rejection of claim 1 above.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Wilson provides the motivation to combine the references as Wilson suggests AAVrh91 is a suitable substitute for AAV9.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant’s arguments directed to the previous rejection of claim 4, the rejection has been withdrawn because Applicant has canceled claim 4, however, since the limitations of the claim have been included in the newly amended claim 1, the arguments directed to Wilson will be addressed below.
Regarding the arguments, see pages 6-7 of the Remarks, filed 27 April 2026, with respect to Wilson describing alternative AAV capsids have been fully considered but they are not found persuasive.
In response to applicant's argument that Wilson is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, while Wilson does not teach GLP-1, the reference was included because Wilson suggests the AAVrh91 and AAV9 capsid are suitable substitutes for gene therapy.
In response to applicant's argument that Wilson does not suggest the combination of GLP-1 with the vector genome of amended claim 1 nor provides motivation to package GLP-1 in an AAVrh91 capsid, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claims 5, 9, 11-15, 17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Kwiatkowski et al., (WO 2020/053815 A1, published 19 March 2020, of record) in view of Hinderer et al. (WO 2017/024198 A1, published 09 February 2017, IDS ref., of record) and Wilson et al. (US 2022/0389457 A1, priority to provisional application 62/924,970, filed on 23 October 2019, of record) as applied to claims 1, 6, and 20 above, and further in view of Chen et al. (Human Gene Therapy Methods 24, August 2013, IDS ref., of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claims 5, 9, and 12, Kwiatkowski in view of Hinderer teach a vector comprising a regulatable promoter (claim 9d) (Hinderer et al., para. [00065]), the sequence encoding the fusion protein, and a polyadenylation signal (Hinderer et al., para. [00066]); however, are silent to an inducible gene expression system.
Chen teaches adeno-associated virus (AAV)-based vector with tissue-specific gene regulation (p. 270, Introduction). Chen teaches a nucleic acid constructs comprising FRB p65, the activation domain comprising the FRB (FKBP12-rapamycin binding) domain of human FRAP (FKBP12-rapamycin-associated protein) (claim 9a) fused to a portion of human NF-KB p65 (claim 12); ZFHD1 3x FKBP fusion (claim 9b), hGH poly A; and the vector comprising twelve ZFHD sites followed by a minimal IL2 promoter (claim 9c) and reporter gene (see Fig. 1 below).
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Chen teaches gene regulation is achieved by reconstituting two split domains for DNA binding and transcription activation of a transcription factor using a dimerizing inducer, rapamycin, an orally bioavailable drug (p. 273, Results). Chen teaches the rapamycin-induced system combines extremely low basal expression with highly inducible, dose dependent expression in order to achieve pharmacological control over the levels and kinetics of therapeutic gene expression (p. 270, 2nd column). The rapamycin-induced system of Chen reads as wherein the presence of an effective amount of a rapamycin induces expression of the transgene in a host cell.
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the inducible expression system of Chen with the expression cassette of Kwiatkowski in view of Hinderer and Wilson because Chen teaches the usefulness of viral vector-mediated gene transfer for therapeutic applications would be greatly enhanced if the expression of the transgene could be regulated with respect to both the timing and level of gene expression (p. 270, 2nd column). Additionally, inducible gene expression systems offer control for gene therapy, facilitating precise regulation of therapeutic genes, adjusting expression levels, and manage side effects by minimizing leaky expression and enabling rapid shutdown. One would be motivated to utilize the inducible expression system of Chen with the expression cassette of Kwiatkowski in view of Hinderer and Wilson because Chen teaches the inducible expression system provided reversible, reproducible, and dose-dependent gene regulation (Abstract and p. 275, 2nd column).
Regarding claim 11, Chen teaches a vector comprising FKBP (Fig. 1A and Fig. 2B, E, and F). Chen does not disclose any mutant variants of the FKBP, which suggests native FKBP was utilized, absent evidence to the contrary.
Regarding claim 13 and 14, Chen teaches a CMV promoter (claim 14), which is a constitutive promoter (claim 13). Chen teaches a rapamycin-induced system, therefore, the CMV promoter is considered part of this regulatable system, thus, a regulatable promoter.
Regarding claim 15, Chen teaches the viral vector comprises IRES and T2A (Fig. 1).
Regarding claim 17, Chen teaches 12 copies of the binding site for ZFHD (Fig. 1).
Regarding claim 19, Chen teaches a viral vector comprising the p65 transactivation domain, FRAP, a DNA binding domain comprising a ZFHD, three FKBP subunit genes, and 12 copies of the ZFHD (which comprises 8 copies) (Fig. 1). Chen does not teach a sequence encoding a fusion protein comprising a GLP-1 analog and a human IgG4 Fc. Kwiatkowski in view of Hinderer teaches the sequence encoding a fusion protein comprising a GLP-1 analog and a human IgG4 Fc. Therefore, Kwiatkowski in view of Hinderer, Wilson, and Chen teaches all of the limitations of the claim.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant’s arguments, see pages 7-8 of the Remarks, filed 27 April 2026, with respect to Chen not suggesting the combination of GLP-1 with the vector genome of amended claim 1 have been fully considered and are persuasive. Specifically, due to the amendment to the independent claim to include the AAVrh91 capsid overcomes the previous rejection of Kwiatkowski in view of Hinderer, therefore, rejection under 103 has been withdrawn.
However, upon further consideration, new grounds of rejection are made in view of Kwiatkowski, Hinderer, Wilson, and Chen. While Chen does not teach the AAVrh91 capsid, the combined teachings of Kwiatkowski, Hinderer, and Wilson suggests AAVrh91 would be a suitable substitute for the AAV9 capsid, as discussed in the rejection of claim 1 above.
Regarding the arguments, see pages 7-8 of the Remarks, filed 27 April 2026, with respect to Chen have been fully considered but they are not found persuasive.
In response to applicant's argument that Chen is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, while Chen does not teach GLP-1, the reference was included because Chen teaches AAV-based vector with tissue-specific gene regulation comprising tissue-specific gene regulation, a vector comprising FKBP, a regulatable CMV promoter, viral vector comprising IRES and T2A, ZFHD binding sites, and p65 transactivation domain, FRAP.
In response to applicant's argument that Chen does not suggest the combination of GLP-1 with the vector genome of amended claim 1 nor provides motivation to package GLP-1 in an AAVrh91 capsid, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claims 7 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Kwiatkowski et al., (WO 2020/053815 A1, published 19 March 2020, of record) in view of Hinderer et al. (WO 2017/024198 A1, published 09 February 2017, IDS ref., of record), Wilson et al. (US 2022/0389457 A1, priority to provisional application 62/924,970, filed on 23 October 2019, of record), and Chen et al. (Human Gene Therapy Methods 24, August 2013, IDS ref., of record) as applied to claims 5, 9, 11-15, 17, and 19 above, and further in view of Buck et al. (Int. J. Mol. Sci. 2020, published 12 June 2020, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claim 7, Kwiatkowski in view of Hinderer, Wilson, and Chen render obvious the viral vector of claim 5. Hinderer teaches vectors comprising a CB7 promoter (para. [00065]). Hinderer teaches expression cassettes may contain other processing signals such as polyadenylation (poly A) signals (para. [00066]).
Kwiatkowski in view of Hinderer, Wilson, and Chen are silent to a rabbit globin poly A.
However, Buck teaches polyadenylation sequences in rAAV-gene cassettes for efficient pre-mRNA processing (p. 16). Buck et al. teach several examples of poly A sequences utilized in rAAV gene cassettes, to include SV40, hGH polyA, and rabbit poly A (Table 5).
Therefore, it would have been obvious to substitute a rabbit poly A taught by Buck for the SV40 or hGH polyA utilized by Chen with a reasonable expectation of success because SV40, hGH polyA, and rabbit poly A are all known as commonly used poly A signals in viral vector systems for gene expression and one would have had a reasonable expectation they would have worked in the same manner. One would be motivated to substitute a rabbit poly A taught by Buck for the SV40 or hGH polyA utilized by Chen because rabbit poly A sequence is significantly shorter than the alternatives, thus, making it ideal for maximizing the limited packaging capacity of AAV vectors.
Additionally, substitution of one known element for another known element, the elements having equivalent effect, is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See MPEP 2143(I).
Regarding claim 18, SEQ ID NO: 16 was not known in the prior art, however, Kwiatkowski in view of Hinderer, Wilson, Chen, and Buck render obvious all of the components of the vector genome. The instant specification states at p. 31, “The vector genome (or rAAV genome) comprises 5' and 3' AAV inverted terminal repeats (ITRs), the polynucleotide sequence encoding the fusion protein, and regulatory sequences which direct insertion of the polynucleotide sequence encoding the fusion protein to the genome of a host cell.” As indicated in the rejection of claims 1, 7, and 9, the sequence of the polynucleotide sequence encoding the fusion protein is obvious, as are the ITRs and regulatory sequences. This suggests it would have been obvious to combine the sequences of these vector genome components to arrive at a sequence at least 70% identical to SEQ ID NO: 16 with a reasonable expectation of success because all of the components of the vector genome were known in the art according to the teachings of Kwiatkowski in view of Hinderer, Wilson, Chen, and Buck. One would be motivated to combine the sequences of these vector genome components to arrive at a sequence at least 70% identical to SEQ ID NO: 16 because to utilize the inducible expression system of Chen with the expression cassette of Kwiatkowski in view of Hinderer because Chen teaches the inducible expression system provided reversible, reproducible, and dose-dependent gene regulation (Abstract and p. 275, 2nd column).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant’s arguments, see pages 8-9 of the Remarks, filed 27 April 2026, with respect to Kwiatkowski, Hinderer, nor Chen requiring an AAVrh91 capsid have been fully considered and are persuasive. Specifically, due to the amendment to the independent claim to include the AAVrh91 capsid overcomes the previous rejection of Kwiatkowski in view of Hinderer, therefore, rejection under 103 has been withdrawn.
However, upon further consideration, new grounds of rejection are made in view of Kwiatkowski, Hinderer, Wilson, Chen, and Buck. The combined teachings of Kwiatkowski, Hinderer, and Wilson suggests AAVrh91 would be a suitable substitute for the AAV9 capsid, as discussed in the rejection of claim 1 above.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the combination of Kwiatkowski, Hinderer, Wilson, and Chen provides the necessary suggestions and motivation to combine a GLP-1 with the vector genome as described in amended claim 1; and Buck describes the polyadenylation sequences and/or vector regulatory elements as required by claims 7 and 18.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Kwiatkowski et al., (WO 2020/053815 A1, published 19 March 2020, of record) in view of Hinderer et al. (WO 2017/024198 A1, published 09 February 2017, IDS ref, of record), Wilson et al. (US 2022/0389457 A1, priority to provisional application 62/924,970, filed on 23 October 2019, of record), and Chen et al. (Human Gene Therapy Methods 24, August 2013, IDS ref., of record) as applied to claims 5, 9, 11-15, 17, and 19 above, and further in view of Tong et al. (Curr Mol Pharmacol. 2015, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the new rejection below.
Regarding claim 10, Kwiatkowski in view of Hinderer, Wilson, and Chen are silent to the FKBP subunit gene sequences sharing about 70% to about 85% identity with each other.
However, Tong teaches FKBP subunits, such as FKBP12 and FKBP12.6 share 83% identity (p. 1, Introduction). Tong teaches FKBP12 and FKBP12.6 are the smallest subunits and both comprise one PPIase domain (p. 1, Introduction and Fig. 1). Tong teaches the PPIase domain is involved in mediating protein-protein interaction (p. 16, Conclusion). Tong teaches FKBP12 and FKBP12.6 preferentially associate with different molecules (p. 3, Section 2.1.2), which suggests a potential for differential regulation.
Therefore, it would have been obvious to one of ordinary skill in the art to combine the heterogeneous FKBP12 subunits taught by Tong with the viral vector system of Kwiatkowski in view of Hinderer, Wilson, and Chen with a reasonable expectation of success because the teachings of Tong suggest a potential for differential regulation and in a viral vector system for chemically induced dimerization (CID), this could facilitate precise control over protein interactions and incorporating both FKBP12 and FKBP12.6 in a viral vector system could allow for differential regulation. One would be motivated to combine the heterogeneous FKBP12 subunits taught by Tong with the viral vector system of Kwiatkowski in view of Hinderer, Wilson, and Chen because a system using both FKBP12 and FKBP12.6, with their variations in binding affinity, could allow for more precise binding.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant’s arguments, see pages 9-10 of the Remarks, filed 27 April 2026, with respect to Tong not teaching or suggesting an AAVrh91 capsid have been fully considered and are persuasive. Specifically, due to the amendment to the independent claim to include the AAVrh91 capsid overcomes the previous rejection of Kwiatkowski in view of Hinderer, therefore, rejection under 103 has been withdrawn.
However, upon further consideration, new grounds of rejection are made in view of Kwiatkowski, Hinderer, Wilson, Chen, and Tong. The combined teachings of Kwiatkowski, Hinderer, and Wilson suggests AAVrh91 would be a suitable substitute for the AAV9 capsid, as discussed in the rejection of claim 1 above.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the combination of Kwiatkowski, Hinderer, Wilson, and Chen provides the necessary suggestions and motivation to combine a GLP-1 with the vector genome as described in amended claim 1; and Tong describes FKBP subunit gene sequences which share 70-85% identity with each other, as required by claim 10.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Kwiatkowski et al., (WO 2020/053815 A1, published 19 March 2020, of record) in view of Hinderer et al. (WO 2017/024198 A1, published 09 February 2017, IDS ref, of record), Wilson et al. (US 2022/0389457 A1, priority to provisional application 62/924,970, filed on 23 October 2019, of record), and Chen et al. (Human Gene Therapy Methods 24, August 2013, IDS ref., of record) as applied to claims 5, 9, 11-15, 17, and 19 above, and further in view of Chng et al. (mAbs 7:2, 403-412; March/April 2015) and Saphire et al. (The Journal of Biological Chemistry, Vol. 273, No. 45, Issue of November 6, pp. 29764-29769, 1998).
This is a new rejection, necessitated by Applicant’s amendments to the claims.
Regarding claim 16, Chen teaches the utilization of T2A linker sequences.
However, Chen does not teach the vector comprising a 2A linker selected from GT2A_V1 or GT2A_V2 consisting of amino acid sequences of SEQ ID NO: 21 or SEQ ID NO: 22. It is noted for the record that instant SEQ ID NO: 21 and 22 comprise the known GT2A linker consensus sequence followed by a nuclear localization sequence (NLS) following the 2A cleavage site.
Chng teaches the GT2A sequence is GSGEGRGSLLTCGDVEENPGP (Fig. 1). Chng teaches 2A linked genes are translated in one open reading frame and “self-cleavage” occurs co-translationally (p. 404, Introduction). Chng teaches T2A from Thosea asigna virus have been used widely in biomedical research, wherein T2A had the highest cleavage efficiency when compared to other 2A peptides using in vitro transcription/translation experiments (p. 404, Introduction). Chng teaches adding GSG linkers immediately preceding 2A has been shown to improve 2A cleave efficiency (p. 404, Introduction). Chng teaches the sequences for the 2A peptides were designed based on what was known in the art (p. 409, Vector construction). The GT2A sequence of Chng is identical to the first 21 AA of instant SEQ ID NO: 21.
Chng does not teach the addition of a NLS sequence. However, the NLS sequence found in instant SEQ ID NO: 21 was known in the art.
Saphire teaches the C-Myc NLS sequence is AAKRVKLD (Fig. 1), which is the NLS sequence found in instant SEQ ID NO: 21. Saphire teaches c-Myc NLS are active as nuclear import directing signals in a permeabilized cell nuclear import assay (p. 29767, Discussion). Saphire teaches the NLS is usually located in an internal portion of the primary structure and must function without impinging upon the folding and functional requirements of the specific protein in which it resides (p. 29768, Discussion).
Therefore, it would have been obvious to one of ordinary skill in the art to include the GT2A sequence of Chng with the NLS sequence of Saphire in the vector of Kwiatkowski in view of Hinderer, Wilson, and Chen with a reasonable expectation of success because both features were known in the art to be utilized in vector systems for protein delivery. Additionally, Chng teaches T2A have been used widely in biomedical research, wherein T2A had the highest cleavage efficiency when compared to other 2A peptides using in vitro transcription/translation experiments and NLS sequences are known to facilitate nuclear import of proteins. One would be motivated to include the GT2A sequence of Chng with the NLS sequence of Saphire in the vector of Kwiatkowski in view of Hinderer, Wilson, and Chen because 2A facilitate efficient cleavage of the protein of interest from the remainder of the gene expression system and the NLS sequence would facilitate transport of said protein of interest into the nucleus of a cell.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
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 and 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 7-8 of copending Application No. 18/843,440 (reference application).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the rejection below.
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
Regarding claim 1, reference claims 3 and 4 reads on all of the limitations of instant claim 1, to include SEQ ID NO: 14 of both applications being 100% identical. See alignment results below:
PNG
media_image3.png
139
653
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Greyscale
Reference claim 3 discloses SEQ ID NO: 14 which is the amino acid sequence. The reference claims do not specifically disclose a viral vector comprising SEQ ID NO: 15, however, the coding sequence, SEQ ID NO: 14 would necessarily be at least 75% identical to SEQ ID NO: 15, as it is the nucleic acid sequence which encodes SEQ ID NO: 14. Reference claim 4 discloses wherein the viral vector comprises the AAV capsid of AAVrh91.
Regarding claim 6, reference claim 7 discloses all of the limitations of instant claim 6.
Regarding claim 7, reference claim 8 discloses all of the limitations of instant claim 7.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Traversal
Applicant’s arguments, see page 10 of the Remarks, filed 27 April 2026, with respect to the co-pending application not describing the rAAV vector composition as stated in the amended claims have been fully considered are not found persuasive. However, the previous rejection has been withdrawn due to Applicant’s amendments to the claims and a revised rejection using the same references has been set forth above. Specifically, while the instant claims have been amended, the co-pending application still describes the rAAV vector composition of the instant claims. As such, the co-pending application was not found to be patentably distinct from the instant claims.
Claims 1, 5, and 6-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3-5, and 7-8 of copending Application No. 18/843,440 in view of Domenger et al. (Human Molecular Genetics, 2019, of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the rejection below.
The reference claims anticipate instant claims 1-4 and 6-7, therefore, also render them obvious.
Regarding claim 5, reference claim 5 discloses an inducible expression system, a regulatable promoter, and the sequence encoding the fusion protein.
However, the reference claim is silent to the composition comprising a viral vector and a polyadenylation signal. Domenger teaches components of a typical AAV expression vector comprise a polyadenylation signal, as this marks the end of the transcriptional cassette (Fig. 1).
Therefore, it would have been obvious to one of ordinary skill in the art to include a viral vector and polyadenylation signal to effectively express the composition comprising the expression cassette of the fusion protein of the reference claim with a reasonable expectation of success because this method of delivery is well known in the art. One would be motivated to include a viral vector and polyadenylation signal to effectively express the composition comprising the expression cassette of the fusion protein of the reference claim because Domenger teaches recombinant adeno-associated viruses (AAV) are under intensive investigation in numerous clinical trials after they have emerged as a highly promising vector for human gene therapy (Abstract).
This is a provisional nonstatutory double patenting rejection.
Response to Traversal
Applicant’s arguments, see pages 10-11 of the Remarks, filed 27 April 2026, with respect to the co-pending application not describing the rAAV vector composition as stated in the amended claims have been fully considered are not found persuasive. However, the previous rejection has been withdrawn due to Applicant’s amendments to the claims and a revised rejection using the same references has been set forth above. Specifically, while the instant claims have been amended, the co-pending application still describes the rAAV vector composition of the instant claims. As such, the co-pending application was not found to be patentably distinct from the instant claims.
In response to applicant's argument that Domenger does not describe the use of an AAVrh91 capsid, nor does Domenger describe the use of GLP-1, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Claims 1, 5, 6-7, 9, 12-15, 17, and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 7-9, 12-17, and 21 of copending Application No. 18/843,440 in view of Domenger et al. (Human Molecular Genetics, 2019, of record) and further in view of Chen et al., (Human Gene Therapy Methods, 2013, IDS ref., of record).
This is a new rejection, necessitated by Applicant’s amendments to the claims. A response to Applicant’s traversal follows the rejection below.
The reference claims anticipate instant claims 1 and 6-7, therefore, also render them obvious. The reference claims in view of Domenger render obvious instant claim 5, therefore, are also included in this rejection.
Regarding claim 9, reference claim 9 in view of Domenger disclose all the limitations of the inducible gene expression system of instant claim 9, however, is silent to the specific minimal promoter.
Chen teaches a nucleic acid constructs comprising FRB p65, the activation domain composed of the FRB (FKBP12-rapamycin binding) domain of human FRAP (FKBP12-rapamycin-associated protein) fused to a portion of human NF-KB p65; hGH poly A and SV40 poly A, and a minimal IL-2 promoter (Fig. 1). Therefore, it would have been obvious to one of ordinary skill in the art to utilize the minimal IL-2 promoter in an expression cassette comprising the same elements as the reference claim because the minimal IL-2 promoter was known in the art as an effective promoter in this type of expression system. One would be motivated to utilize the minimal IL-2 promoter because the minimal IL-2 promoter is known in the art to create activation-inducible transgene expression.
Regarding claims 12-15, 17, and 19, reference claims 12-15, 16, and 17, respectively, in view of Domenger and Chen teach all of the limitations of instant claims 12-15, 17, and 19, as the reference claims are identical to the instant claims with the exception of the composition being a viral vector which has been made obvious by Domenger and Chen, above.
Regarding claim 20, reference claim 21 discloses a composition formulated to be administered, which reads as a pharmaceutical composition which would comprise an aqueous liquid in order to achieve the appropriate dose and for administration purposes. Reference claim 21 refers to a composition, but is silent to the composition comprising a viral vector, which has been made obvious by Domenger and Chen, above.
This is a provisional nonstatutory double patenting rejection.
Response to Traversal
Applicant’s arguments, see pages 11-12 of the Remarks, filed 27 April 2026, with respect to the co-pending application not describing the rAAV vector composition as stated in the amended claims have been fully considered are not found persuasive. However, the previous rejection has been withdrawn due to Applicant’s amendments to the claims and a revised rejection using the same references has been set forth above. Specifically, while the instant claims have been amended, the co-pending application still describes the rAAV vector composition of the instant claims. As such, the co-pending application was not found to be patentably distinct from the instant claims.
In response to applicant's argument that Domenger or Chen do not describe the use of an AAVrh91 capsid, nor do Domenger or Chen describe the use of GLP-1, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kim et al. (PLoS ONE, April 2011, Vol. 6, Issue 4)
Kim teaches the benefits of 2A peptides, to include the GT2A peptide, and note biomedical researchers could adopt 2A technology when bicistronic or multicistronic expression is required. Kim teaches NLS attached to the N-terminus of a protein facilitates nuclear transport of said protein.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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