DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 25 November 2025 have been entered. Claims 1-9, 19-21, 23-26, 30, and 38 were previously pending in the application. Claims 6, 19-21, 30 have been cancelled, and new claims 40-43 have been added by Applicant. Claims 1-5, 7-9, 23-26, 38, and 40-43 are currently pending in the application. Claims 1, 9, and 26 are independent claims.
The following election of species remains in effect in the instant application:
Symptoms: d. Albuminuria,
AAV virion serotypes: a. AAV9,
Routes of administration: a. Intravenous,
Promoters: f. CMV actin- Globin (CAG) Hybrid Promoter,
Claims 2-4, 7-8, and 25 remain withdrawn from consideration as being directed to a nonelected species.
Claims 1, 5, 9, 23-24, 26, 38, and 40-43 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/US2021/018613, filed 18 February 2021, which claims priority to U.S. provisional application 62/979,252, filed 20 February 2020.
Thus, the earliest possible priority for the instant application is 20 February 2020.
Specification
The objection to the specification of the disclosure for the Brief Description of the Drawings not describing each panel and for the inclusion of trade names and/or marks used in commerce without the corresponding generic terminology and/or proper symbols, is withdrawn in view of the amendment to the specification.
Claim Objections
The objection to amended claim 1 for reciting “SPL” without first writing out the full term is withdrawn in view of the amendment to claim 1.
Claim Rejections - 35 USC § 112(b)
The rejection of amended and cancelled claims 5, 6, and 26 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out and distinctly claim the subject matter which the inventor(s) regards as the invention for indefinite language is withdrawn in view of Applicant’s cancellation of claim 6 and amendments to the claims such that amended claim 5 now recites “at least 5% reduction in the level of albumin in the urine of the subject as compared to the level of albumin in the urine prior to the administering” and amended claim 26 now recites “a first copy” and “a second copy” to clarify the duplicate recitations of an AAV ITR.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, original, and cancelled claims 1, 5-6, 9, 19, 23-24, 26, 30, and 38 under 35 U.S.C. 103 as being unpatentable over Choi & Saba (2019, Advances in Biological Regulation, 71, 128-140, available online 25 September 2018, IDS); in view of Inagaki et al. (2006, Molecular Therapy, 14(1), 45-53); Wang et al. (2016, Int. J. Med. Sci.¸13(4), 286-291); and Earley et al. (2020, Human Gene Therapy, 31(3-4), 151-162, published online 14 February 2020), is withdrawn over cancelled claims 6, 19, and 30, maintained over amended, previously presented, and original claims 1, 5, 9, 23-24, 26, and 38, and newly applied to new claims 40-43. 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’s amendments to claims 1, 5, 9, 23-24, 26, and 38 primarily address formalities and issues of indefiniteness and do not alter the scope of the recited claims sufficiently to overcome the rejection of record. New claims 40 and 42-43 recite limitations which were addressed in the prior office action: new claim 40 recites rAAV vector compositions addressed previously for amended claim 26 and wherein the SPL is a human SPL addressed previously for previously presented claim 23; new claim 42 recites that the active promoter comprises a CMV promoter or a CAG hybrid promoter previously addressed for cancelled claim 30; and new claim 43 recites intravenous administration (an elected species) addressed previously for previously presented claim 24.
Regarding new claim 41, Wang was cited for teaching rAAV genomes for gene therapy comprising two ITRs and a CAG promoter operably linked to a transgene of interest [Figure 1A]. Additionally, Earley was cited for teaching that AAV viral vectors have been successful used in laboratory and clinical settings for efficient gene delivery, wherein 96% of the AAV genome is replaced with a gene cassette of interest, leaving only the 145 bp inverted terminal repeat (ITR) sequences [abstract]. Earley also teaches that the ITR sequences are required for genome rescue, replication, packaging, and vector persistence [abstract], and that the ITRs flank the ends of the genome, fold back on themselves to form hairpin structures, and play a fundamental role in the life cycle of AAV by containing the replication of origin, packaging signals, and the ability to confer persistence to AAV genomes after infection [column 1 ¶ 1- column 2 ¶ 2]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to include ITR sequences flanking a transgene of interest in an AAV vector to ensure genome rescue, replication, packaging, and vector persistence.
Wang further teaches that AAV2 is the most widely used AAV serotype in human trials [column 1 ¶ 1], and the use of AAV2 ITRs in an rAAV8 vector for gene delivery [column 3 ¶ 4].
Further, Earley teaches that class I ITRs (AAV2 and 3) generate the highest expression across multiple cell lines in vitro, and that serotype ITR sequence may have multiple levels of influence on transgene expression cassettes independent of promoter selection [abstract, column 16 ¶ 2]. Early also teaches that rAAV vector production platforms rely on an AAV2 Rep-AAV2 ITR replication and packaging system [column 3 ¶ 2], and that AAV2 ITRs have the ability to promote enough transgene expression in vivo to have biological effects at the cellular level [column 13 ¶ 2, column 16 ¶ 2]. Therefore, an ordinarily skilled artisan at the time of filing would have been motivated to use an AAV2 ITR for high level expression which is capable of promoting enough transgene expression in vivo to have biological effects at the cellular level.
Given the motivation taught by Wang and Earley to include ITR sequences flanking a transgene of interest in an AAV vector to ensure genome rescue, replication, packaging, and vector persistence and the motivation taught by Earley to use an AAV2 ITR for high level expression which is capable of promoting enough transgene expression in vivo to have biological effects at the cellular level, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the method of Choi to include AAV2 ITRs as the first copy and the second copy of the AAV ITRs with a reasonable expectation of success.
Therefore, Applicant’s amendments do not overcome a finding of obviousness under 35 U.S.C. 103 over Choi, Inagaki, Wang, and Earley.
Applicant argues that:
There is no valid reason to use AAV9 mediated gene delivery for treating or preventing SPLIS;
There is no reasonable expectation of success in using AAV9 mediated gene delivery for treating or preventing SPLIS;
Choi teaches away from using rAAV9 gene therapy;
A POSITA would not be motivated to use a constitutive promoter for expressing SPL since such promoters can cause high expression levels which could results in the recipient developing cancer;
The claimed method provides unexpected results; and
The claimed invention fulfills long felt but unsolved need by providing a treatment for SPLIS.
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), Applicant contests that Choi does not teach a method for treating SPLIS in a subject, the method comprising administering to the subject a therapeutically effective dose of a vector comprising a nucleic acid encoding SPL because Choi teaches introducing a vector comprising a nucleic acid encoding SPL into mouse embryonic stem cells to replace the mouse S1PL gene with the human S1PL gene. However, the fact that Choi may teach the replacement of gene in a mouse embryonic stem cell does not preclude Choi from also teaching the administration to a subject having SPLIS. As cited in the prior action, Choi teaches an SPL gene replacement strategy for treating SPLIS in a subject [page 136 ¶ 4-5, page 138 ¶ 2].
Choi was not cited for teaching that the gene delivery mechanism for the SPL gene therapy to treat SPLIS was via an rAAV9 vector.
Inagaki was cited for teaching rAAV9 as a gene delivery mechanism, wherein rAAV9 systemically infected all 10 tissues analyzed (e.g., liver, skeletal muscle, heart, pancreas, brain, lung, spleen, kidney, intestine, and testis) with considerable efficiency by tail vein injection [abstract, column 1 ¶ 1- column 2 ¶ 1, column 8 ¶ 2]. Inagaki teaches that rAAV9 is a robust vector for gene therapy application and that rAAV9 transduced most of these tissues more efficiently than an alternative AAV serotype (e.g., AAV8) [abstract Figure 4]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use an rAAV9 viral vector for the delivery of a gene therapy product to a variety of organs and tissues to treat a disease with multiple organ involvement.
Additionally, Choi explicitly teaches that “gene correction, gene replacement, or enzyme replacement therapies are the only strategies with the potential to resolve all the biochemical defects associated with SPL insufficiency” [page 138 ¶ 2]. Therefore, a person of ordinary skill in the art would expect that supplying SPL (e.g., via gene correction, gene replacement, or enzyme replacement) to a subject having SPLIS would in fact treat the SPLIS.
Regarding Applicant’s argument 2), Applicant argues that mice having integrated SPL in the genome under the gene’s own promoter results in transgene expression in all the right locations and so does not provide a reasonable expectation of success in treating SPLIS by using an rAAV for expressing SPL under the control of a constitutive promoter and only in tissues targeted by the rAAV. Again, note that Choi did not ONLY teach a mouse with a human SPL transgene. Choi specifically and explicitly taught gene replacement and enzyme replacement as therapeutic strategies with the potential to resolve all the biochemical defects associated with SPL insufficiency [page 138 ¶ 2]. As such, Choi provides a reasonable expectation of success for administering a gene encoding SPL. Also note that the claims as written do not require any particle tissues to be transduced or any particular expression levels or patterns of the SPL gene.
Regarding Applicant’s argument 3), Applicant asserts that Choi does not teach or suggest using AAV gene therapy for treating SPLIS because Choi suggests supportive therapy, chemical chaperones, using sphingosine kinase inhibitors, monoclonal S1P specific antibodies, product replacement, and substrate depletion. However, the fact that Choi proposes multiple approaches for managing patients with SPLIS is not a teaching away from another approach which is also taught, e.g., gene therapy.
Applicant also asserts that “gene correction, gene replacement, and enzyme replacement therapies” does not encompass an AAV gene therapy because the claimed method does not correct the gene, replace a mutant gene, nor deliver the enzyme. However, introduction of a functional gene encoding a functional enzyme to a patient is a gene replacement in that the patient’s defective mutant copy of the gene is dysfunction or nonfunctional, and so the provided gene is functionally replacing the defective gene to restore a desired phenotype. Additionally, supplying a gene encoding a functional enzyme, which is capable of being expressed in the subject, is also a form of enzyme replacement in that the gene is used to producer, and thereby provide, the deficient enzyme to the patient. Therefore, Choi is not teaching away from using SPL gene therapy for treating SPLIS.
Regarding Applicant’s argument 4), note that Applicant has not claimed any particular expression level from the constitutive promoter. Note also that any administration to treat a degenerative disease which promotes growth and survival necessarily has a risk of excessive growth and/or survival promotion. Therefore, any such treatment would necessarily be titrated for the specific application to provide sufficient expression of the pro-growth/pro-survival factor without inducing cancer mechanisms. Such titration can occur at multiple levels of design and administration of a therapeutic, including structural components such as the nucleic acid sequence encoding and regulating the gene therapy transgene (e.g., promoters, codon usage, introns, WPRE, etc.) as well as administration variables such as dose and administration frequency. Therefore, the selection of a particular promoter is just one of many variables to be considered when designing a gene therapy construct; a strong promoter will not necessarily produce excessive amounts of the transgene and so will not necessarily be unwanted. In fact, Wang was cited for teaching that the CAG promoter drives more efficient transgene expression in some cell lines compared with the CMV promoter [column 3 ¶ 2], which may be desirable, for example, to allow lower doses of vector to be administered, thereby reducing the risk of AAV vector-related side effects.
Regarding Applicant’s argument 5) that the instantly claimed method provides unexpected results, as supported by Dr. Saba’s declaration that it was not predictable that AAV9 capsids could target the relevant tissues and deliver a level of SPL encoding nucleic acid sufficient to treat SPLIS, note that the instant claims do not recite any particular tissue transduction or expression. The instant claims also do not recite a level of SPL encoding nucleic acid to be delivered to any tissues, nor any level of expression to be obtained in any tissues.
Applicant further asserts that “improved versions of AAV9”, Anc80 an M6, unexpectedly did not provide significant gain in life-span of SPL-KO mice, while AAV9 that targets kidney cells with lesser efficiency than Anc80 did provide significant gain in life-span of SPL-mice, as shown in Figure 1 of the Declaration.
Note, however, that the evidence of unexpected results provided in the Declaration and instant disclosure are not commensurate in scope with the instantly recited claims. It is noted that any evidence of unexpected results must be commensurate in scope with the claimed invention, and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).
Specifically, firstly, the instant claims recite “AAV serotype 9 capsid protein”, which encompasses AAV9 variants, and therefore encompasses the Anc80 and M6 variants which Applicant is asserting do not provide benefit over the mock treatment [Declaration Figure 1]. Secondly, a gain in lifespan is not a claimed limitation. The instant claims merely recite “a method of treating” and “thereby treating the SPLIS in the subject” (claim 1), which encompasses any amount of “treatment” as any improvement of any symptom or condition associated with the SPLIS. Thirdly, the instant claims do not recite any particular tissue to be targeted/transduced by the vector nor any particular expression levels within any particular tissues.
Also, note that while Declaration Figure 1 shows a statistically significant increase in lifespan for mice treated with the rAAV9 gene therapy compared to a mock gene therapy, it does not show a significant difference between treatment with an rAAV9 gene therapy vs. an Anc80 (or even M6) gene therapy.
Dr. Saba refers to Figures 3A and 3C of the instant Drawings to indicate that the rAAV9 gene therapy construct does not provide significant expression in the kidneys, which organ is involved in the mortality of SPLIS. Figure 3A shows a western blot depicting SPL levels in the kidney, adrenal gland, or liver following administration of the rAAV9 in knockout mice, from which Dr. Saba determines a lack of significant expression in the kidney following administration of the rAAV. However, note that the loading control (GAPDH) for the rAAV treated kidney sample is dramatically reduced compared to each of the other samples, making conclusions regarding the expression in the kidney unreliable.
Additionally, the HET sample depicted in Figure 3A, which still comprises one functional copy of the endogenous gene, does not show a visible band for SPL in the kidney, even though the HET kidney sample shows a higher loading than presented for the rAAV9-administered KO kidney (e.g., higher GAPDH). Further, Inagaki was cited for teaching that AAV9 transduces the 10 tissues they analyzed, including the kidney, with considerable efficiency by tail vein injection [abstract, column 1 ¶ 1- column 2 ¶ 1, column 8 ¶ 2]. Wang teaches that the CAG promoter is active in kidney cells (e.g., HEK293T cells) [column 6 ¶ 2, Figure 2]. Therefore, given that the kidney expression of SPL is not detected in the HET mouse, that AAV9 is known to transduce mouse kidneys, and that the CAG promoter is active in kidney cells, an ordinarily skilled artisan could conclude alternatively that a kidney-specific SPL is either not detectable by the particular antibody at the particular position on the blot OR that kidney expression at a level detectable under such blotting condition is not necessary to achieve a normal phenotype (as seen in the HET mouse in Figures 8 and 10 of the instant Drawings). As such, the absence of a SPL band in the blot depicted in Figure 3A is not convincing evidence of unexpected results.
Improved symptoms/conditions associated with SPLIS, such as an increase in lifespan, improved albuminuria, or improved gross pallor in kidneys (as asserted in the Declaration and shown in Figures 4D-4G of the instant Drawings), additionally would not be unexpected following administration of an rAAV9 vector delivering an SPL gene to a subject having SPLIS, given the teachings of Choi, Inagaki, Wang, and Earley, as discussed above and in the prior action. Replacing a defective causative gene with a functional version of the gene expressing a functional gene product is a well-known approach to remedy a genetic defect which a POSITA would expect to result in some level of improvement of the adverse condition caused by the defective gene. Specifically, given the teachings of Choi that “gene correction, gene replacement, or enzyme replacement therapies are the only strategies with the potential to resolve all the biochemical defects associated with SPL insufficiency” [page 138 ¶ 2], a POSITA would expect that a gene therapy which delivers a functional SPL gene to a subject having SPLIS would in fact result in improvement of defects which underly the shortened lifespan associated with SPLIS, particularly given the broad tropism of AAV9, as taught by Inagaki.
Regarding Applicant’s argument 6), that the claimed invention fulfills a long felt but unsolved need by providing a treatment for SPLIS, note that MPEP 716.04(I) states:
“Establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. In re Gershon, 372 F.2d 535, 539, 152 USPQ 602, 605 (CCPA 1967) ("Since the alleged problem in this case was first recognized by appellants, and others apparently have not yet become aware of its existence, it goes without saying that there could not possibly be any evidence of either a long felt need in the . . . art for a solution to a problem of dubious existence or failure of others skilled in the art who unsuccessfully attempted to solve a problem of which they were not aware."); Orthopedic Equipment Co., Inc. v. All Orthopedic Appliances, Inc., 707 F.2d 1376, 217 USPQ 1281 (Fed. Cir. 1983) (Although the claimed invention achieved the desirable result of reducing inventories, there was no evidence of any prior unsuccessful attempts to do so.). Second, the long-felt need must not have been satisfied by another before the invention by the inventor. Newell Companies v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988) (Although at one time there was a long-felt need for a "do-it-yourself" window shade material which was adjustable without the use of tools, a prior art product fulfilled the need by using a scored plastic material which could be torn. "[O]nce another supplied the key element, there was no long-felt need or, indeed, a problem to be solved".) Third, the invention must in fact satisfy the long-felt need. In re Cavanagh, 436 F.2d 491, 168 USPQ 466 (CCPA 1971). See Ex parte Thompson, Appeal 2011-011620 (March 21, 2014) (informative) for the board’s analysis of the above-mentioned three factors in reversing an obviousness rejection due to evidence of long felt need.”
In the instant case, Choi, which was co-authored by an inventor of the instant application, Dr. Julie Saba, is titled “Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism”, indicating that the SPLIS condition was newly recognized by the inventor with the publication of Choi in 2018. Additionally, Choi states, “In 2017-2018, a series of reports identified a novel childhood syndrome caused by recessive mutations in the human SGPL1 gene that encodes SPL” [page 129 ¶ 4] and “We now refer to this condition as SPL Insufficiency Syndrome, or SPLIS [page 130 ¶ 1]. Therefore, given that the condition was only recognized within 3 years of the effective filing date of the instant application, and then first named thereafter by the inventors, the lack of treatment for SPLIS is not an art recognized problem which existed in the art for a long period of time without solution.
Further, Applicant has not provided any objective evidence to indicate that anyone else has attempted and failed to meet the need of a treatment for SPLIS.
Finally, Applicant has indicated that the long felt need is for a curative treatment to SPLIS, which has not been shown by Applicant in any evidence provided in the specification or in the provided Declaration.
Accordingly, Applicant has not established that the claimed method overcomes a long felt need sufficient to overcome a finding of obviousness.
Therefore, Applicants arguments do not overcome a finding of obviousness under 35 U.S.C. 103 over Choi, Inagaki, Wang, and Earley, 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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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