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 .
Application Status
This action is written in response to applicant’s correspondence received on 10/24/2024. Claims 1-16 are pending. All pending claims are currently under examination.
Claim Interpretation
Regarding claim 1, claim 1 recites a capsid protein comprising an amino acid substitution at position T265 relative to SEQ ID NO: 1. Furthermore, dependent claim 2 recites that additional mutations are present in SEQ ID NO: 1. Claim 1 therefore can broadly be interpreted to encompass any number of additional mutations because the claim can broadly be interpreted to be drawn to SEQ ID NO: 1 with any additional mutations. This interpretation is consistent with how the claims are presently construed because dependent claims 2 and 6-7 recite additional mutations not previously recited in claim 1. Thus, the rejections are made in light of the interpretation that the claims can include additional mutations in SEQ ID NO: 1, as SEQ ID NO: 1 is recited with open claim language of “comprising” a substitution at T265 which allows for other mutations.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4, 8-9, and 13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Regarding claim 1, claim 1 is broadly drawn to an amino acid sequence encoded by SEQ ID NO: 1 with a substitution at position T265 (see claim interpretation above). Note that because claim 1 can comprise any additional sequence changes, recitation of “AAVrh74 capsid” does not add structurally defined limitations, as long as the sequence remains a capsid protein. Claim 1 is therefore broadly drawn to an amino acid sequence comprising a mutation at position T265 and any additional mutations encoding a capsid protein. As shown in GenBank AAO88184 (hereafter ‘184, GenBank Accession Number AAO88184, published 2003), ‘184 is an AAV capsid protein which is 88% identical to instant SEQ ID NO: 1 and comprises a T265 mutation (see alignment on page 1, and title on page 2). Thus, claim 1 is broadly drawn to a naturally occurring product of nature as it reads on the amino acid sequence of the AAV capsid ‘184. Claim 1 does not recite any additional limitations which turn the claim into a practical application (Step 2A, prong 2) or transform the claim into significantly more because not markedly different characteristics are recited in the claim (Step 2B). Claim 1 is therefore not subject matter eligible and is rejected under 101.
Regarding claim 2, ‘184 comprises a substitution relative to T494 when compared with instant SEQ ID NO: 1 (see alignment on page 1 of ‘184). Thus, claim 2 is drawn to the naturally occurring capsid protein taught in ‘184 without additional limitations.
Regarding claim 4, as discussed above, ‘184 comprises a substitution of T265 relative to SEQ ID NO: 1 (see page 1 of ‘184 for alignment).
Regarding claims 8-9, as evidenced by page 2 of ‘184, the capsid protein is encoded in a nucleic acid sequence (i.e., “CDS,” coding region) and is therefore a naturally occurring nucleic acid sequence within the viral genome comprising the ‘184 gene. With regards to claim 9, ‘184 teaches that the capsid protein is an AAV particle, where furthermore any of the other viral genes encoded by the parvovirus of ‘184 can be broadly interpreted to be a “gene of interest.” Thus, claims 8-9 are broadly drawn to the naturally occurring genome and gene products of the parvovirus encoding ‘184 (see pages 2-3 of ‘184).
Regarding claim 13, claim 13 is broadly drawn to the viral particle of claim 9, where a pharmaceutically acceptable carrier can be interpreted to be either the viral capsid itself or a naturally occurring medium in which such a virus could exist (e.g., solution comprising water). The limitations of claim 13 are therefore drawn to natural products of nature.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 4, 8-9, and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by GenBank AAO88184 (hereafter ‘184, GenBank Accession Number AAO88184, published 2003).
Regarding claim 1, claim 1 is broadly drawn to an amino acid sequence encoded by SEQ ID NO: 1 with a substitution at position T265 (see claim interpretation above). Note that because claim 1 can comprise any additional sequence changes, recitation of “AAVrh74 capsid” does not add structurally defined limitations, as long as the sequence remains a capsid protein. Claim 1 is therefore broadly drawn to an amino acid sequence comprising a mutation at position T265 and any additional mutations encoding a capsid protein. As shown in GenBank AAO88184 (hereafter ‘184, GenBank Accession Number AAO88184, published 2003), ‘184 is an AAV capsid protein which is 88% identical to instant SEQ ID NO: 1 and comprises a T265 mutation (see alignment on page 1, and title on page 2). Thus, claim 1 is broadly drawn to the amino acid sequence of the AAV capsid ‘184.
Regarding claim 2, ‘184 comprises a substitution relative to T494 when compared with instant SEQ ID NO: 1 (see alignment on page 1 of ‘184).
Regarding claim 4, as discussed above, ‘184 comprises a substitution of T265 relative to SEQ ID NO: 1 (see page 1 of ‘184 for alignment).
Regarding claims 8-9, as evidenced by page 2 of ‘184, the capsid protein is encoded in a nucleic acid sequence (i.e., “CDS,” coding region) and is therefore encoded in nucleic acid sequence within the viral genome comprising the ‘184 gene as taught by ‘184 (page 2).
With regards to claim 9, ‘184 teaches that the capsid protein is an AAV particle, where furthermore any of the other viral genes encoded by the parvovirus of ‘184 can be broadly interpreted to be a “gene of interest.” Thus, claims 8-9 are broadly drawn to the genome and gene products of the parvovirus encoding ‘184 (see pages 2-3 of ‘184).
Regarding claim 13, claim 13 is broadly drawn to the viral particle of claim 9, where a pharmaceutically acceptable carrier can be interpreted to be either the viral capsid itself or a naturally occurring medium in which such a virus could exist (e.g., solution comprising water).
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.
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, 3-5, and 8-16 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski (WO 2017/106236 A1) in view of Asher (Asher DR et al. Expert Opin Biol Ther. 2020 Mar;20(3):263-274). The rejection is further evidenced by NCBI AF513852 (hereafter ‘852, NCBI BLAST Accession Number AF513852, published 2002).
Regarding claim 1, Samulski is a patent document which focuses on engineering AAV capsids for enhanced delivery (Title, Abstract, and throughout). Samulski teaches that:
“This study dissected rAAV capsid architecture to develop an engineering strategy designed to improve muscle transduction. Contrary to rAAV2 265 insertion mutants, the deletion of position 265 from the rAAV1 capsid provided the highest level of enhancement for both transgene delivery and expression in muscle tissue,” (paragraph 8).
And:
“the deletion of T265 resulted in substantial detargeting of the liver,” (page 88, final paragraph, and Figure 14E).
Thus, Samulski has already taught a deletion/substitution strategy with AAV capsids at position 265 in order to improve transgene delivery and expression in muscle tissue, where furthermore Samulski teaches that such mutations are known to have the advantage of detargeting the liver. Samulski furthermore teaches that their strategies can be applied to AAV vectors such as AAV8 (e.g., see claims 1-5).
While Samulski teaches the T265 mutational strategy as well as benefits to applying the T265 mutational strategy to AAV vectors such as AAV8 (liver detargeting, improved transduction characteristics), Samulski does not teach that the AAV capsid is the AAVrh74 capsid.
Asher is a research article that focuses on gene therapy to deliver therapeutics to muscle cells using AAV particles (Title, Abstract, and throughout). Samulski and Asher therefore directly overlap in subject matter and field of endeavor. Furthermore, Asher teaches that the used the AAVrh74 capsid delivery system, specifically because of its advantages including high transduction efficiency to muscle cells and low seroprevalence which allows its application to more patients (see page 270 left column, paragraphs 2-3 and page 268). Thus, Asher not only teaches that AAVrh74 is a known capsid but also teaches motivational teachings for its use due to its characteristics (e.g., high transduction efficiency in muscle cells). Furthermore, Asher teaches that AAV8, as taught by Samulski, is in the same phylogenetic category as AAVrh74, where the two capsids share close homology (page 268, left column, first paragraph). As evidenced by ‘852, ‘852 is shown in alignment with instant SEQ ID NO: 1 (i.e., wildtype rh74, as recited in claim 1). As shown in ‘852, ‘852 is the sequence of AAV8 and shares 96% positive alignment with instant SEQ ID NO: 1 (page 1 of ‘852). Thus, as taught by Asher and evidenced by ‘852, AAV8 and rh74 (instant SEQ ID NO: 1) indeed share a high degree of structural homology (see pages 1-3 of ‘852, and page 268, left column, first paragraph of Asher). Thus, there is a high degree of predictability that structural and amino acid modifications performed on AAV8 would apply to the rh74 capsid.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the AAV8 T265 capsid modifications taught by Samulski to the AAVrh74 capsids taught by Asher because such a combination is the simple combination of known prior art elements with predictable success. Furthermore, the combination is not simply a combining of elements, the practitioner would be motivated to use the rh74 capsids taught by Asher because these capsids are known to be particularly useful for transducing muscle cells (Asher, above). Furthermore, given the high degree of sequence homology between AAV8 (Samulski) and rh74 (Asher) the sequence manipulation of T265/deletions taught by Samulski can predictably be applied to the rh74 capsid taught by Asher.
Regarding claim 3, Samulski teaches that the T265 position is deleted (paragraph 8).
Regarding claim 4, Samulski teaches that the residue can be substituted (e.g., paragraph 9). Furthermore, given that Samulski already teaches that T265 is deleted, the practitioner can immediately envision making a substitution at this residue because the exact position (265) has already been identified, where changes (i.e., deletions) were already shown to be tolerated by the AAV capsids (Samulski, e.g., paragraph 8).
Regarding claim 5, Samulski teaches that the T265 residue is deleted or substituted (paragraphs 8-9). Samulski does not teach that T265 is specifically substituted with F or G.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the T265 deletion/substitution to arrive at an F or G substitution because such a modification is obvious to try, where the practitioner is choosing from a finite number of identified solutions. In the present case, Samulski has already taught that the position T265 should be targeted for either deletion or substitution, and the practitioner is selecting form only 19 other amino acids to arrive at the present invention. Furthermore, the results are predictable because Samulski has already taught that T265 can be deleted where the AAV capsid tolerates this deletion with added benefits to the capsid (e.g., paragraph 8).
Regarding claim 8, Samulski teaches that the capsid protein is encoded in a nucleic acid (e.g., paragraph 123).
Regarding claim 9 and 11-12, Samulski teaches that the viral capsid particles can comprise genes of interest to be delivered in the capsids, including therapeutic proteins such as dystrophin (e.g., paragraphs 149-150).
Regarding claim 10, Samulski teaches that the genes can be delivered and expressed using muscle-specific promoters (paragraph 163). Asher also teaches such delivery constructs including the use of the muscle-specific MHCK7 promoter (e.g., page 267 right column final two paragraphs and Figure 5).
Regarding claim 13, Samulski teaches that the compositions can be comprised in a pharmaceutically acceptable carrier (e.g., paragraph 188).
Regarding claims 14-15, Samulski teaches that the capsid and compositions can be administered to a human subject (e.g., see paragraphs 187-189).
Regarding claim 16, Samulski teaches that the composition is administered to a subject suffering from muscular dystrophy such as DMD (e.g., paragraph 203).
Claims 2 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Samulski (WO 2017/106236 A1) and Asher (Asher DR et al. Expert Opin Biol Ther. 2020 Mar;20(3):263-274) as applied to claims 1, 3-5, and 8-16, above, and further in view of Yazicioglu (WO 2013/158879 A1). The rejection is further evidenced by NCBI AF513852 (hereafter ‘852, NCBI BLAST Accession Number AF513852, published 2002).
A discussion of Samulski and Asher is given above with respect to claims 1, 3-5, and 8-16 and is incorporated herein. Samulski and Asher render obvious the rh74 variant recited in claim 1, where furthermore Samulski further renders obvious the deletion of T265.
Regarding claims 2 and 6-7, Samulski and Asher do not teach Y447F and Y733F mutations.
Yazicioglu is a patent document which focuses on gene therapy and AAV variants for delivery (Title, Abstract, and throughout). Yazicioglu therefore directly overlaps in subject matter with Samulski and Asher because each of these documents has the same goal and similar design principles. Furthermore, Yazicioglu, like Samulski and Asher, teach the AAV8 capsid vector (e.g., Table 3). Yazicioglu teaches that the Y447F and Y733F mutations in the AAV8 capsid protein are known mutations which benefit capsid design by increasing transduction efficiency (see page 19, lines 30-35 and Table 3, top of page 33). Furthermore, as discussed above, Asher teaches that AAV8 and rh74 share highly similar homology, as further evidenced by ‘852 (see alignment of ‘852 AAV8 with instant SEQ ID NO: 1, page 268 left column of Asher).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the rh74 capsid protein comprising a T265 mutation as rendered obvious by Samulski and Asher to further include Y447F and Y733F mutations taught by Yazicioglu because such mutational strategies are already known in the art as taught by Yazicioglu, who teaches the motivational teaching that such 447 and 733 mutations increase the transduction efficiency of the viral capsid. Furthermore, the result is predictable because Yazicioglu teaches their strategy in AAV8 which shares a high structural and sequence similarity with the rh74 capsid taught by Asher.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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