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 .
Applicant’s election without traverse of SEQ ID NO: 13, constitutive promoter, and enhanced chicken β-actin promoter in the reply filed on 7/15/26 is acknowledged.
Claims 14 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/15/26.
Improper Markush Rejection
Claims 1, 2, 4, 6, 8-13, 16-18, 20, and 21 are rejected on the judicially-created 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). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims are directed to a multitude of amino acid sequences that encode an ABDA4 minigene, each having a different sequence and activity. Each of the minigene sequences have different sequences that include different exons(s) and regulatory sequences.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled:
(A) All alternatives have a common property or activity; and
(B) (1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or
(B) (2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together.
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific amino acid sequence is dependent upon the specific sequence. There is no expectation that any one of the amino acid sequences as claimed can be substituted for any of the other with a different sequence with the expectation of the same activity.
As set forth in MPEP2117, “Note that where a Markush group includes only materials from a recognized scientific class of equivalent materials or from an art-recognized class, "the mere existence of such a group in an application tend[s] to prove the equivalence of its members and when one of them [is] anticipated the group [is] therefore rendered unpatentable, in the absence of some convincing evidence of some degree of non-equivalency of one or more of the remaining members." In re Ruff, 256 F.2d 590, 598-99, 118 USPQ 340, 348 (CCPA 1958)("[A]ctual equivalence is not enough to justify refusal of a patent on one member of a group when another member is in the prior art. The equivalence must be disclosed in the prior art or be obvious within the terms of Section 103." Id. at 599, 118 USPQ at 348).”
In the instant case, art against any one amino acid sequence would not be evidence against any of the remaining members that have different sequences and do not have identical activity.
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 9 and 10 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 9 recites “assessing” lipofuscin and/or A2E concentration, which is not a clear step. The metes and bounds of the term “assessing” cannot be clearly ascertained. It is not clear what specific step is required to assess lipofuscin and/or A2E concentration.
The claim also recites that a decrease in lipofuscin and/or A2E concentration “indicates” maintenance of ONL thickness. The metes and bounds of “indicates” are not definite. It is not clear whether a decrease in lipofuscin and/or A2E concentration results in a determination that ONL thickness is maintained or if a decrease in lipofuscin and/or A2E concentration merely suggests a possibility.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 4, 6, 8, 11-13, and 16-21 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Khanna et al. (WO 2020/214809 A2)
Khanna et al. teaches the instant ABCA4 minigene encoding the amino acid sequences of SEQ ID NOs: 9-14 and 20-24 (sequence listing).
Khanna et al. teaches: In some aspects the disclosure relates to isolated nucleic acids encoding an ABCA4 minigene. Generally, an isolated nucleic acid encoding a minigene ( e.g. ., a therapeutic minigene, such as an ABCA4 minigene) is between about 10% and about 99% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 40% about 50%, about 60%, about 70%, about 75%, about 80%, about 90%, about 99%, etc.) truncated with respect to a nucleic acid sequence encoding the corresponding naturally-occurring wild-type protein (e.g., SEQ ID NO: 1). The truncations may be continuous (e.g., single, continuous truncation of amino acid residues) or discontinuous (e.g., two or more truncations of amino acids, for example truncation of two or more domains, that are separated by one or more peptides). For example, in some embodiments, a minigene encoding a Mini ABCA4 protein is between about 61% and truncated (e.g., comprises about 50% of the nucleic acid sequence) compared to a wild-type ABCA4 gene (e.g., SEQ ID NO: 1). In some embodiments, an ABCA4 minigene comprises (or consists of) the nucleic acid sequence set forth in any one of SEQ ID NOs: 3-8 and 15-19. In some embodiments, an ABCA4 minigene encodes a protein (referred to as a MiniABCA4 protein) that comprises (or consists of) an amino acid sequence set forth in any one of SEQ ID NOs: 9-14 and 20-24 (instant claims 1, 18, and 19).
Khanna et al. teaches: Examples of constitutive promoters include, without limitation, the retroviral Rous sarcoma virus (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer) [see, e.g., Boshart et al., Cell, 41:521-530 (1985)], the SV40 promoter, the dihydrofolate reductase promoter, the b-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EF1 a promoter [Invitrogen] . In some embodiments, a promoter comprises a chicken beta-actin (CBA) promoter. In some embodiments, a promoter is an enhanced chicken b-actin promoter. In some embodiments, a promoter is a U6 promoter. In some embodiments, a promoter is a chicken beta-actin (CBA) promoter (instant claims 11-13).
Khanna et al. teaches: In some embodiments, an expression cassette encoding a minigene is flanked by one or more viral replication sequences, for example lentiviral long terminal repeats (LTRs) or adeno-associated virus (AAV) inverted terminal repeats (ITRs) (instant claim 16).
Khanna et al. teaches: In some embodiments, the isolated nucleic acid (e.g., the rAAV vector) comprises at least one ITR having a serotype selected from AAV1, AAV2, AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAV10, AAV11, and variants thereof (instant claim 17)
Khanna et al. teaches: In some aspects, the disclosure relates to compositions and methods useful for treating certain genetic diseases, for example Stargardt disease. The disclosure is based, in part, on isolated nucleic acids and gene therapy vectors, such as viral ( e.g. ., rAAV) vectors, comprising one or more gene fragments encoding a therapeutic gene product, such as a MiniABCA4 protein (e.g., the gene product of an ABCA4 minigene) (instant claim 21).
Khanna et al. teaches: In some embodiments, an rAAV is formulated for delivery to the eye. In some embodiments, an rAAV is formulated for delivery to photoreceptor cells or retinal pigmented endothelium (RPE). In some aspects, the disclosure provides a method for delivering a transgene to a cell, the method comprising administering an isolated nucleic acid or an rAAV as described herein to a cell (instant claim 1).
Khanna et al. teaches: An effective amount may also depend on the mode of administration. For example, targeting an ocular ( e.g. ., photoreceptor, retinal, etc.) tissue by intrastromal administration or subcutaneous injection may require different (e.g., higher or lower) doses, in some cases, than targeting an ocular (e.g., photoreceptor, retinal, etc.) tissue by another method (e.g., systemic administration, topical administration).
Khanna et al. teaches: In some embodiments, the administration is via injection, optionally subretinal injection or intravitreal injection or suprachoroidal injection. In some embodiments, the injection is topical administration (e.g., topical administration to an eye). In some cases, multiple doses of a rAAV are administered (instant claim 20).
Therefore, Khanna et al. teaches a method of administering to the retina of a subject an AAV comprising a transgene encoding an ABCA4 minigene encoding the amino acid sequence set forth in instant SEQ ID NOs: 9-14 and 20-24. The reference is not required to teach the intended outcome of the preamble, which would necessarily flow from the only recited method step which is taught by Khanna et al.
Instant claims 2, 4, 6, 8, and 10 recite outcomes rather than additional method steps. The outcomes would necessarily flow from the recited method step.
Therefore, the claims are anticipated by Khanna et al.
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.
With regards to the preamble intended outcomes:
Claim(s) 1, 2, 4, 6, 8-13, and 16-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khanna et al. (WO 2020/214809 A2), in view of Dyka et al. (Human Gene Therapy, 30, 11, 1361-1370, 2019).
Khanna et al. teaches the instant ABCA4 minigene encoding the amino acid sequences of SEQ ID NOs: 9-14 and 20-24 (sequence listing).
Khanna et al. teaches: In some aspects the disclosure relates to isolated nucleic acids encoding an ABCA4 minigene. Generally, an isolated nucleic acid encoding a minigene ( e.g. ., a therapeutic minigene, such as an ABCA4 minigene) is between about 10% and about 99% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 40% about 50%, about 60%, about 70%, about 75%, about 80%, about 90%, about 99%, etc.) truncated with respect to a nucleic acid sequence encoding the corresponding naturally-occurring wild-type protein (e.g., SEQ ID NO: 1). The truncations may be continuous (e.g., single, continuous truncation of amino acid residues) or discontinuous (e.g., two or more truncations of amino acids, for example truncation of two or more domains, that are separated by one or more peptides). For example, in some embodiments, a minigene encoding a Mini ABCA4 protein is between about 61% and truncated (e.g., comprises about 50% of the nucleic acid sequence) compared to a wild-type ABCA4 gene (e.g., SEQ ID NO: 1). In some embodiments, an ABCA4 minigene comprises (or consists of) the nucleic acid sequence set forth in any one of SEQ ID NOs: 3-8 and 15-19. In some embodiments, an ABCA4 minigene encodes a protein (referred to as a MiniABCA4 protein) that comprises (or consists of) an amino acid sequence set forth in any one of SEQ ID NOs: 9-14 and 20-24 (instant claims 1, 18, and 19).
Khanna et al. teaches: Examples of constitutive promoters include, without limitation, the retroviral Rous sarcoma virus (RSV) LTR promoter (optionally with the RSV enhancer), the cytomegalovirus (CMV) promoter (optionally with the CMV enhancer) [see, e.g., Boshart et al., Cell, 41:521-530 (1985)], the SV40 promoter, the dihydrofolate reductase promoter, the b-actin promoter, the phosphoglycerol kinase (PGK) promoter, and the EF1 a promoter [Invitrogen] . In some embodiments, a promoter comprises a chicken beta-actin (CBA) promoter. In some embodiments, a promoter is an enhanced chicken b-actin promoter. In some embodiments, a promoter is a U6 promoter. In some embodiments, a promoter is a chicken beta-actin (CBA) promoter (instant claims 11-13).
Khanna et al. teaches: In some embodiments, an expression cassette encoding a minigene is flanked by one or more viral replication sequences, for example lentiviral long terminal repeats (LTRs) or adeno-associated virus (AAV) inverted terminal repeats (ITRs) (instant claim 16).
Khanna et al. teaches: In some embodiments, the isolated nucleic acid (e.g., the rAAV vector) comprises at least one ITR having a serotype selected from AAV1, AAV2, AAV5, AAV6, AAV6.2, AAV7, AAV8, AAV9, AAV10, AAV11, and variants thereof (instant claim 17)
Khanna et al. teaches: In some aspects, the disclosure relates to compositions and methods useful for treating certain genetic diseases, for example Stargardt disease. The disclosure is based, in part, on isolated nucleic acids and gene therapy vectors, such as viral ( e.g. ., rAAV) vectors, comprising one or more gene fragments encoding a therapeutic gene product, such as a MiniABCA4 protein (e.g., the gene product of an ABCA4 minigene) (instant claim 21).
Khanna et al. teaches: In some embodiments, an rAAV is formulated for delivery to the eye. In some embodiments, an rAAV is formulated for delivery to photoreceptor cells or retinal pigmented endothelium (RPE). In some aspects, the disclosure provides a method for delivering a transgene to a cell, the method comprising administering an isolated nucleic acid or an rAAV as described herein to a cell (instant claim 1).
Khanna et al. teaches: An effective amount may also depend on the mode of administration. For example, targeting an ocular ( e.g. ., photoreceptor, retinal, etc.) tissue by intrastromal administration or subcutaneous injection may require different (e.g., higher or lower) doses, in some cases, than targeting an ocular (e.g., photoreceptor, retinal, etc.) tissue by another method (e.g., systemic administration, topical administration).
Khanna et al. teaches: In some embodiments, the administration is via injection, optionally subretinal injection or intravitreal injection or suprachoroidal injection. In some embodiments, the injection is topical administration (e.g., topical administration to an eye). In some cases, multiple doses of a rAAV are administered (instant claim 20).
Therefore, Khanna et al. teaches a method of administering to the retina of a subject an AAV comprising a transgene encoding an ABCA4 minigene encoding the amino acid sequence set forth in instant SEQ ID NOs: 9-14 and 20-24. The reference is not required to teach the intended outcome of the preamble, which would necessarily flow from the only recited method step which is taught by Khanna et al.
Instant claims 2, 4, 6, 8, and 10 recite outcomes rather than additional method steps. The outcomes would necessarily flow from the recited method step.
Khanna et al. does not teach that the method increases the thickness of the outer nuclear layer of the retina or maintains outer nuclear layer thickness.
However, one would expect for the method of Khanna et al. to result in one of these outcomes because Dyka et al. demonstrate delivery of ABCA4 and an increase in the ONL of the retina.
Dyka et al. teach: Autosomal recessive Stargardt disease is the most common inherited macular degeneration in humans. It is caused by mutations in the retina-specific ATP binding cassette transporter A4 (ABCA4) that is essential for the clearance of all-trans-retinal from photoreceptor cells. Loss of this function results in the accumulation of toxic bisretinoids in the outer segment disk membranes and their subsequent transfer into adjacent retinal pigment epithelium (RPE) cells. This ultimately leads to the Stargardt disease phenotype of increased retinal autofluorescence and progressive RPE and photoreceptor cell loss. In this study, we have evaluated the in vitro expression of ABCA4 using three options: overlap, transplicing, and hybrid ABCA4 dual vector systems. The hybrid system was the most efficient of these dual vector alternatives and used to express the full-length ABCA4 in Abca4-/- mice. The full-length ABCA4 protein correctly localized to photoreceptor outer segments. Moreover, treatment of Abca4-/- mice with this ABCA4 hybrid dual vector system resulted in a reduced accumulation of the lipofuscin/N-retinylidene-N-retinylethanolamine (A2E) autofluorescence in vivo, and retinal A2E quantification supported these findings. These results show that the hybrid AAV dual vector option is both safe and therapeutic in mice, and the delivered ABCA4 transgene is functional and has a significant effect on reducing A2E accumulation in the Abca4-/- mouse model of Stargardt disease (abstract).
Although Khanna et al. does not teach assessing lipofuscin or A2E concentration, it would have been obvious to assess lipofuscin and A2E concentration because Dyka et al. teach that delivery of ABCA4 resulted in reduced accumulation of the lipofuscin/N-retinylidene-N-retinylethanolamine (A2E). Therefore, it would have been obvious to assess lipofuscin and A2E concentration and correlate to the presence of Stargardt disease (instant claim 9).
Dyka demonstrates increase in ONL thickness in Figure 3B after delivery of ABCA4 dual vector system (AAV8 subretinal injection) compared to control 3C. Therefore, one would have reasonably expected for the method of Khanna et al. to result in this increase in ONL thickness. One would have reasonably expected to maintain ONL thickness given Figure 3B of Dyka et al.
Conclusion
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/AMY ROSE HUDSON/ Primary Examiner, Art Unit 1636
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