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 claims 73-90 with species election of SEQ ID NO:6 in the reply filed on January 16, 2026 is acknowledged.
Status of Claims
Claims 73-92 are currently pending in the instant application. Claims 91-92 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Accordingly, claims 73-90 are under examination on the merits in the instant application.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on August 29, 2023 and August 8, 2024 have been considered by the examiner. Note that the non-English language foreign patent document citation numbers 001 and 002 in the IDS filed on August 29, 2023 are considered only insofar as the one-page English language “Bibliographic data” as submitted by applicant.
Claim Objections
Claims 87-88 and 90 are objected to because of the following informalities:
1. “an rAAV” in line 1 of claim 87 and in line 2 of claim 90 should be “the rAAV”.
2. “a composition” in line 1 of claim 88 should be “the composition”.
Appropriate correction is required.
Claim Rejections - Improper Markush Grouping
Claims 73-90 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination of process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP §706.03(y).
The Markush grouping of SEQ ID NOs:2-10 recited in all of claims 73-90 is improper because the alternatives defined by the Markush grouping do not all share a substantial nucleotide sequence similarity. For instance, applicant’s elected SEQ ID NO:6 shares only about 80% sequence identity with SEQ ID NO:10, wherein the 80% sequence identity level comprises no significant fragment (e.g., 500-1000 nucleotides in length) that is identical between the two different SEQ ID NOs. That is, the two nucleotide sequence species share sporadic nucleobase matches throughout the entire 1,602 nucleotides. Hence, there is no core, substantial nucleotide sequence similarity shared by all alternatively recited SEQ ID NOs, which are recited in all of the claims under examination on the merits in the instant application.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternatives within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
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 73-90 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.
Claims 73-90 recite that the coding sequence of RPE65 “is codon-optimized and contains an altered number of CpG dinucleotides as compared to a wildtype RPE65 nucleotide sequence”. Hence, the claimed codon-optimized sequence is required to have an increased number or a decreased number of CpG dinucleotides relative to “a wildtype RPE65 nucleotide sequence”, wherein the increased/decreased number of CpG depends on the exact nucleotide sequence of the “wildtype RPE65”. Now, as written, the claimed “wildtype RPE65 nucleotide sequence” is not claimed by a specific nucleotide sequence thus reads on any available “wildtype” RPE65 nucleotide sequence variants (e.g., transcript variants) comprising a non-identical number of CpG, thereby rendering the “altered number of CpG dinucleotides as compared to a wildtype RPE65 nucleotide sequence” different depending on the exact “wildtype” nucleotide sequence of RPE65. Hence, the “altered number” would differ depending on the user-selected wildtype sequence, thereby rendering the CpG dinucleotide number variable/different/inconsistent depending on the actual “wildtype” sequence selected by different users thus rendering the metes and bounds of the claimed structure unclear.
For examination purpose, the “wildtype RPE65” will be interpreted as SEQ ID NO:1 of the instant application in light of the disclosure in paragraph 0006 disclosing “a wild type RPE65 nucleotide sequence (SEQ ID NO: 1).”
Claims 78 and 86 each depend from claim 73 and claim 79, respectively, and each of claims 78 and 86 recites “wherein the polynucleotide sequence comprises not more than 300 CpG dinucleotides.” It is noted that each of the “polynucleotide sequence” of claim 73 and the “second polynucleotide” of claim 79 is required to have at least 95% sequence identity to one of SEQ ID NOs:2-10. It is noted that 128 is the highest number of CpG in one of the recited SEQ ID NOs, SEQ ID NO:10. As such, it is scientifically impossible for a nucleotide sequence having at least 95% identity to SEQ ID NO:10 comprising 128 CpG dinucleotides to have as many as “300 CpG dinucleotides.” Hence, claims 78 and 86 recite structurally conflicting limitations regarding the number of CpG dinucleotides in the polynucleotide sequence that is at least 95% identical to the recited SEQ ID NOs, thereby rendering the structure of claims 78 and 86 indefinite.
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 73-90 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.
The instant claims are drawn to an rAAV particle comprising a “codon-optimized” RPE65 nucleotide sequence containing “an altered number of CpG dinucleotide” as compared to SEQ ID NO:1, the wild-type, unmodified RPE65 nucleotide sequence, wherein the codon-optimized RPE65 nucleotide sequence is at least 95% identical to one of SEQ ID NOs:2-10.
It is recognized and accepted in the relevant art that the purpose of codon-optimization is to “increase protein expression level by utilizing preferred codons” as evidenced by the instant specification’s disclosure (see paragraph 0068; emphasis added) and as further corroborated by Smith et al. (US 2018/0021458 A1) teaching the following in paragraph 0083: ““Codon optimization” refers to the process of altering a naturally occurring polynucleotide sequence to enhance expression in the target organism, for example, humans.” (emphasis added). As such, it necessarily follows that the claimed “codon-optimized” sequence having at least 95% identity to one of SEQ ID NOs:2-10 must have the function of providing an increased/enhanced expression level of the instantly claimed “RPE65 polypeptide” in a human cell when compared to the human wild-type, unmodified sequence of SEQ ID NO:1.
It is noted that the instant specification, see paragraph 00169, describes in vitro HEK293 cell transfection results, which show reduced RPE65 positive cells in HEK293 cells transfected with RPE001 comprising SEQ ID NO:2 (CpG increased to 24 from 21), RPE002 comprising SEQ ID NO:6 (CpG decreased to 10) with hGHpA, and RPE003 comprising SEQ ID NO:3 (CpG decreased to zero) compared to the wild-type sequence of SEQ ID NO:1 (CpG number is 21). It is also noted that the specification’s Example 4 pertaining to in vivo mouse model is incomplete and deficient in adequately describing RPE65 expression in the mouse model injected with RPE003, RPE004, RPE006, and RPE007 as evidenced by the following disclosure in paragraph 00178, which is essentially the final paragraph of the specification’s disclosure as shown below, wherein underline has been added for emphasis.
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As shown above, the specification’s disclosure pertaining to the in vivo mouse model study abrupted concluded and thus is incomplete and deficient as the results pertaining to “the expression level of human RPE65 protein” in “samples of mouse eye tissues” that “were collected” are not disclosed. Hence, the in vitro HEK293 cell line transfection disclosure showing reduced, not increased/enhanced, expression levels of RPE65 by the constructs mentioned above comprising SEQ ID NOs:2-3 and 6 claimed in the instant case clearly establishes a high level of unpredictability pertaining to the claimed codon-optimized sequences, which apparently have another layer of unpredictability such that the actual protein expression level also depends on the type of a polyA sequence included in the construct in view of the instant specification’s disclosure such that RPE002 comprising SEQ ID NO:6 and a polyA sequence of hGHpA reduced RPE65 expression, whereas RPE006 comprising the same sequence of SEQ ID NO:6 but with a polyA sequence of SV40pA increased RPE65 expression when compared to SEQ ID NO:1. See paragraph 00169. Hence, the instant specification in and of itself demonstrates a high level of unpredictability pertaining to the nucleotide sequences having an altered (both increased and decreased) number of CpG dinucleotides compared to the wild-type sequence of SEQ ID NO:1, wherein the altered nucleotide sequences’ activity is also disclosed to highly depend on the polyA sequence (hGHpA vs. SV40pA). Hence, the two species – one comprising SEQ ID NO:6 (CpG number reduced to 10) with CAG promoter and SV40pA and the other comprising SEQ ID NO:10 (CpG number increased to 128) with CAG promoter and SV40pA – that actually showed increased/enhanced RPE65 expression levels compared to the non-codon-optimized, wild-type sequence of SEQ ID NO:1 are not a representative, sufficient number of structural variants having at least 95% sequence identity to SEQ ID NOs:2-10 having both increased and decreased numbers of CpG dinucleotides compared to SEQ ID NO:1 in view of the high level of variability/unpredictability of the altered nucleotide sequences as amply explained in detail hereinabove. That is, one of ordinary skill in the art cannot reasonably extrapolate the required structure-function correlation for the claimed genus based on the two aforementioned successful structural species and the aforementioned unsuccessful nucleotide sequences that failed to enhance/increase RPE65 expression compared to SEQ ID NO:1.
See MPEP §2163 for the following: “For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)… If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112(a)” (emphasis added).
In view of the foregoing, the instant specification is found insufficient to adequately describe the entire genus of the claimed composition in such a manner to reasonably convey that the instant co-inventors had possession of the claimed genus as of the filing date sought in the instant application.
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.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 87-88 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claims 87-88 are drawn to a “host cell” comprising an rAAV and a codon-optimized sequence encoding RPE65, wherein the term “host cell” is defined in the instant specification as “a cell that can be used to introduce a vector”, wherein the “host” is defined to “refer to any mammalian subject, particularly humans”. See paragraphs 0044 and 0046. Hence, the “host cell” claimed in claims 87-88 embraces and reads on a human being comprising a cell into which the rAAV of claims 73 and 79 is introduced in light of the specification’s definitions.
Recitation of an “isolated” host cell would be remedial.
Allowable Subject Matter
Applicant’s elected species of SEQ ID NO:6 is found free of the prior art searched by the examiner and the prior art in the IDS submitted by applicant.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635