DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 23 February 2026 have been entered. Claims 1-16, 19, and 21-24 were previously pending in the application. Claims 2-4 have been cancelled by Applicant. Claims 1, 5-16, 19, and 21-24 are currently pending in the application. Claims 1, 8, 13, 14, and 24 are independent claims.
The election of Group I, drawn to a vector, a carrier including the vector, and a pharmaceutical composition comprising the vector, remains in effect in the instant application. The following election of species remains in effect in the instant application:
Nucleotide sequences encoding GIRK2 or a derivative thereof: a. SEQ ID NO: 1 (hGIRK2); and
Insertion peptide sequences: b. SEQ ID NO: 11;
Claims 14-16, 19, and 21-24 remain withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim.
Claims 1 and 5-13 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2020/069613, filed 10 July 2020, which claims priority to EPO 20315148.5, filed 10 April 2020, and EPO 20305734.4, filed 30 June 2020. Filing of a certified copy of the EPO 20315148.5 and EPO 20305734.4, filed 10 October 2022, is acknowledged.
Thus, the earliest possible priority for the instant application is 10 April 2020.
Drawings
The replacement drawing sheets filed 23 February 2026 have not been entered. Although Applicant corrected the issue identified in the prior office action, wherein the view numbers for the partial views for Figures 2 and 3 that appear on multiple sheets are followed by "(FIN)" rather than just a Figure number and capital letter such as FIG. 1A, FIG. 1B, etc.; the figure labels for Figure 3A and Figure 3B in the replacement sheets are not oriented in the same direction as the figure itself. See 37 CFR 1.84(p)(1). Appropriate correction is required.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
The objection to amended and cancelled claims 4 and 10 for reciting “AVV9” is withdrawn in view of the amendment cancelling claim 4 and replacing “AVV9” with “AAV9” in claim 10.
**The following new objections are necessitated by amendments to the claims.
Previously presented claim 6 is newly objected to because of the following informalities: claim 6 recites, “The vector according to claim 4”. However, claim 4 is cancelled and, as such, the actual structural elements which Applicant intends to claim as part of the invention of claim 6 cannot be determined. Appropriate correction is required. Further examination of this claim under 35 U.S.C. 101, 102, 103, 112(a), and double patenting is precluded.
Amended claim 10 is newly objected to because of the following informalities: claim 10 recites “VPA” in line 12, which appears to be a typographical misspelling of “VP1”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, previously presented, and cancelled claims 1-13 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefiniteness is withdrawn in view of Applicant’s amendments to the claims such that the identified issues of indefiniteness have been sufficiently addressed.
**The following new rejection is necessitated by amendments to the claims.
Amended and previously presented claim 1 and 5-13 are newly 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 7-9 and 12-13 are included in this rejection due to their dependence on and/or encompassing of independent claims 1.
Amended independent claim 1 newly recites, “the VP1 capsid protein”, which lacks antecedent basis in the claim in that claim 1 has not prior recitation of any VP1 capsid protein.
As such, the metes and bounds of the claim cannot be determined.
Amended claim 5 has multiple issues of indefiniteness.
Amended claim 5, which depends on independent claim 1, newly recites, “a capsid protein” in lines 3, which is indefinite because it is unclear whether the “a capsid protein” of claim 5 is meant to be the same “a capsid protein” as recited in claim 1 line 5.
Amended claim 5, which depends on independent claim 1, newly recites, “a 7 to 11 amino acid long insertion peptide” in lines 3, which is indefinite because it is unclear whether the “a 7 to 11 amino acid long insertion peptide” of claim 5 is meant to be the same “a 7 to 11 amino acid long insertion peptide” as recited in claim 1 line 5.
Claim 5 recites, “said VP1 capsid protein” in line 4, which lacks antecedent basis because it is unclear whether “said VP1 capsid protein” refers to the “a capsid protein” of claim 5 line 3 or to the “the capsid protein” of claim 1 line 5.
Claim 5 recites, “said peptide” in line 10, which lacks antecedent basis because it is unclear whether “said peptide” refers to the “a 7 to 11 amino acid long insertion peptide” of claim 5 line 3 or to the “a 7 to 11 amino acid long insertion peptide” of claim 1 line 5 and “said insertion peptide” of claim 1 lines 5-6.
Amended claim 5, which depends on independent claim 1, recites, “a pR1.7 promoter” in line 10, which is indefinite because it is unclear whether the “a pR1.7 promoter” of claim 5 is meant to be the same “a PR1.7 promoter” as recited in claim 1 line 7.
As such, the metes and bounds of the claim cannot be determined.
Previously presented claim 6 recites, “The vector according to claim 4”, which is indefinite because claim 4 has been cancelled and, as such, the actual structural elements encompassed by claim 6 cannot be determined. As such, the metes and bounds of the claim cannot be determined. Further examination of this claim under 35 U.S.C. 101, 102, 103, 112(a), and double patenting is precluded.
Amended claim 10 has multiple issues of indefiniteness.
Amended claim 10, which depends on claim 9, which in turn depends on claim 8, which encompasses claim 1, newly recites, “the VP1 capsid protein” in line 6 and “said VP1 capsid protein” in line 10, which lacks antecedent basis because claim 10 has no prior recitations of any VP1 capsid protein before line 6, but additionally recites “a VP1 capsid protein” in line 9. Additionally, claim 1 recites “the VP1 capsid protein” in line 5. Therefore, it is unclear to which VP1 capsid protein “the VP1 capsid protein” and “said VP1 capsid protein of claim 10 are referring.
Amended claim 10 newly recites, “a 7 to 11 amino acid long insertion peptide” in lines 5-6 and line 9 as well as “the insertion peptide” in line 6 and “said peptide” in line 13. Therefore, “the insertion peptide” in line 6 and “said peptide” in line 13 lack antecedent basis because it is unclear to which peptide of the “a 7 to 11 amino acid long insertion peptide” in claim 10 lines 5-6, claim 10 line 9, or claim 1 line 5 the recitations in claim 10 are referring.
As such, the metes and bounds of the claim cannot be determined.
Previously presented claim 11 recites, “wherein the carrier is selected from the group consisting of solid-lipid nanoparticles, chitosan nanoparticles, liposomes, lipoplexes and cationic polymers”, which is indefinite because it is unclear in what way the carriers include the vector of claim 1, which is newly limiting to being an AAV virus. For example, it is unclear whether Applicant intends for the AAV virus of claim 1 to be comprised within the nanoparticles, liposomes, lipoplexes, or cationic polymers such that the carrier is surrounding or encompassing the virus or whether the nanoparticles, liposomes, lipoplexes, or cationic polymer carriers are meant to be additional components which are merely mixed with the virus of claim 1. As such, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 102
The rejection of amended and previously presented claims 1, 8, and 13 under 35 U.S.C. 102(a)(1) as being anticipated by Von der Kammer [US20080038730A1, published 14 February 2008], is withdrawn in view of Applicant’s claims which now recite “which comprises the nucleotide sequence according to SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5” in claim 1 lines 3-4.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, and cancelled claims 1-13 under 35 U.S.C. 103 as being unpatentable over Von der Kammer [US20080038730A1, published 14 February 2008]; in view of NCBI [2018, GenBank, retrieved on 20 November 2025 from: https://www.ncbi.nlm.nih.gov/nuccore/NM_002240.4, published online 01 July 2018]; Schaffer [US20140294771A1, published 02 October 2014], Ye et al. [2015, Human Gene Therapy, 27(1), 72-82]; and Masseck et al. [2014, Neuron, 81, 1263-1273, IDS], is withdrawn over cancelled claims 2-4, withdrawn over previously presented claim 6, and maintained over amended and previously presented claims 1, 5, and 7-13. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to address issues of indefiniteness and to incorporate limitations from cancelled claims 2-4 as well as previously presented claim 5. All limitations newly incorporated into amended claim 1 were addressed in the previous office action.
Regarding the amendment to dependent claims 5 and 10, Applicant added a specific reference sequence for the wild-type AAV9, wherein the insertion position is between amino acids 588 and 589 relative to wild-type AAV9 according to SEQ ID NO: 8. Positions 588 and 589 of instant SEQ ID NO: 8 correspond to positions 590 and 591 of the wild-type AAV9 VP1 sequence taught by Schaffer in Figure 17, as seen below in a partial alignment of the region around amino acids 588-591, wherein amino acids at positions 588-589 of instant SEQ ID NO: 8 are highlighted:
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Schaffer was cited for teaching that the variant AAV comprises a VP1 capsid protein with an 10 amino acid long insertion peptide (e.g., SEQ ID NO: 45) inserted in the GH loop of the AAV9 VP1 capsid protein, wherein the peptide is inserted between amino acids 588 and 589 of the wildtype AAV9 VP1 capsid protein (e.g., GenBank Accession No. AAS99264), and wherein the 10 amino acid long insertion peptide is 100% identical to the amino acid sequence of instant SEQ ID NO: 11 [0074, 0076, 0093, 0104, 0119, 0183, 0211, Table 2, Figure 17, claim 5, 22, 26]. Schaffer additionally teaches wherein the insertion site is a single insertion site between two adjacent amino acids located between amnio acids 590 and 591 of VP1 of any AAV serotype [0075, 103]. As such, Schaffer teaches to insert the 10 bp insertion sequence of instant SEQ ID NO: 11 into the position corresponding to a position between amino acids 588 and 589 of a wild-type AV9 VP1 protein according to instant SEQ ID NO: 8.
Accordingly, Applicant’s amendments do not overcome a finding of obviousness under 35 U.S.C. 103 over Von der Kammer, NCBI, Schaffer, Ye, and Masseck.
Applicant argues that:
Von der Kammer provides no indication how to improve GIRK2 expression, or the improvement of gene expression in general;
A significant technical difference between the presently recited subject matter and that of the combined references is that the increase of the GIRK2 gene expression is in the retina (subretinal injection), whereas Ye deals with AAV containing the promoter PR1.7 for gene therapy and Schaffer deals with AAV comprising an insertion peptide in the capsid protein wherein the amino acid sequence LGETTRP is mentioned in a list of 8 amino acid sequences and AAV modified with the insertion peptides are found to be effective when used by intravitreal injection;
There is no suggestion in the prior art to specifically use an AAV modified with a particular insertion peptide in combination with the promoter PR1.7 in order to improve expression of GIRK2 in the retina, such that making the specific choice of this claimed combination was not part of the skilled person’s routine, nor an arbitrary combination based on the skilled person’s knowledge, but rather an inventive selection of elements that resulted in solving the technical challenge posed, which was to increase the expression of GIRK2 in the retina;
Schaffer relates to intravitreal gene expression, which targets a compartment of the eye which is different that the compartment targeted by the present invention;
Schaffer does not target expression in the retina;
Schaffer’s results in the intravitreal space do not show or suggest the achievement of similar results in the subretinal space because the subretinal space is more sensitive and more technically complex than the intravitreal space; and
None of Schaffer, Ye, Von der Kammer, nor Massek provide any evidence that could have led the inventors down this path of the claimed combination of elements to improve gene expression in the retina and improve cone response to light stimuli in mice treated with the AAV encoding GIRK2.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that 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). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, 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 addition, 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).
Specifically, regarding Applicant’s argument 1), note that Von der Kammer was cited for teaching a gene therapy vector comprising a nucleotide sequence encoding Kir3.2/KCNJ6/GIRK2 [0035-0036, 0039-0040]. Von der Kammer additionally teaches wherein the gene therapy vector either replaces a mutated gene or adds a new gene resulting in the synthesis of a therapeutic protein [0036], wherein the term “gene” “comprises both coding regions (exons) as well as non-coding regions (e.g., non-coding regulatory elements such as promoters or enhancers, introns, leader and trailer sequences)” [0012]. Therefore, Von der Kammer teaches the gene therapy vector to comprise regulatory sequences such as a promoter for expression.
Additionally, Schaffer teaches the expression of genes from the AAV vector under the control of a ubiquitous/ constitutive promoter (e.g., CAG promoter), a photoreceptor-specific promoter (e.g., rhodopsin promoter, rhodopsin kinase promoter, a beta phosphodiesterase gene promoter, a retinitis pigmentosa gene promoter, or an IRBP gene promoter), or an interneuron-specific promoter (e.g., connexin36 promoter) [0009, 0025, 0160, 200-201, 0211-0212].
Ye was cited for teaching the motivation to use a pR1.7 promoter for cone cell specific expression, wherein the pR1.7 promoter is a 1.7 kb L-opsin promoter which achieved strong and specific expression in all primate cone photoreceptors (e.g., L. M. and S cones in the primate retina) with more efficiency than the 2.1 kb L-opsin (PR2.1) promoter, such that the authors chose to use the pR1.7 promoter over other photoreceptor-specific promoters in human patients for expression of a gene therapy construct [abstract, column 15 ¶ 2- column 16 ¶ 1, column 19 ¶ 2].
Further, Masseck teaches the coexpression of heterologous GIRK2 and mammalian short wavelength cone opsin (SWO, the mammalian cone opsin recited in claim 12), such that the combination of GIRK channel (GIRK1 and GIRK2 subunits) and SWO constitute an optogenetic tool for fast, repetitive, and ultra light-sensitive control of Gi/o pathways in specific receptor domains in vivo without supply of any external ligands and represent the tools of choice to understand and dissect the function of Gi/o signals in health and disease [column 2 ¶ 1, column 3 ¶ 1- column 4 ¶ 1, Figure 1]. Masseck also teaches that the SWO activates the GIRK channel current [Figure 1]. Masseck further teaches this light-gated GPCR approach might be application for new therapeutic strategies [column 16 ¶ 3].
Therefore, the combination of Von der Kammer, Schaffer, Ye, and Masseck teach the heterologous expression of GIRK2, wherein the GIRK2 expression is increased relative to the cells without the heterologous GIRK2 gene.
Regarding Applicant’s arguments 2)-5) and 7), note that subretinal injection of the claimed vector is not a required limitation of the claim. Additionally, intravitreal injection, as taught by Schaffer, is a means of introducing a vector for transducing retinal cells [see Schaffer 0198-0199].
Schaffer teaches retinal expression of transgenes delivered by the AAV9 comprising an insertion of LALGETTRPA (SEQ ID NO: 45 identical to instant SEQ ID NO: 11) in the VP1 capsid protein, wherein the AAV virions exhibit greater infectivity of retinal cells when administered via intravitreal injection compared to wild-type AAV, including photoreceptors, retinal ganglion cells, Muller cells, bipolar cells, amacrine cells, horizontal cells, or RPE cells [abstract, 0070-0072, 0093, 0119]. Therefore, Schaffer targets expression in the retina.
Additionally, Schaffer teaches specifically the insertion of the LALGETTRPA (SEQ ID NO: 45/ instant SEQ ID NO: 11) sequence into an AAV9 VP1 capsid protein, as the insertion sequence which facilitates increased retinal expression [0024, 0198, Figure 3, 4, 18]. Therefore, Schaffer provides teachings for the specific modified peptide for retinal cell transduction.
As discussed above, Ye was cited for teaching the motivation to use a pR1.7 promoter for cone cell specific expression, wherein the pR1.7 promoter is a 1.7 kb L-opsin promoter which achieved strong and specific expression in all primate cone photoreceptors (e.g., L. M. and S cones in the primate retina) with more efficiency than the 2.1 kb L-opsin (PR2.1) promoter, such that the authors chose to use the pR1.7 promoter over other photoreceptor-specific promoters in human patients for expression of a gene therapy construct [abstract, column 15 ¶ 2- column 16 ¶ 1, column 19 ¶ 2].
Together, Schaffer and Ye provide the teachings and motivations to specifically combine a retinal cell-specific AAV9 vector having an insertion sequence according to instant SEQ ID NO: 11 with the photoreceptor-specific promoter for expression of a transgene in photoreceptor cells.
Regarding Applicant’s argument 6), note again that the claims as written do not require subretinal delivery of the claimed vector. Nor do the claims as written require retinal expression of the claimed vector. Therefore, Schaffer’s results in the intravitreal space, as discussed above, are sufficient to provide motivation for using the claimed AAV9 capsid variant.
Accordingly, Applicant’s arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Von der Kammer, NCBI, Schaffer, Ye, and Masseck, and the rejection is maintained.
Conclusion
No claim is 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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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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