DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 25 September 2025 have been entered. Claims 1-15 and 22 were previously pending in the application. Claims 2 and 8 have been cancelled, and new claims 23-26 have been added by Applicant. Claims 1, 3-7, 9-15, and 22-26 are currently pending in the application. Claims 1 and 10 are independent claims. The following election of species remains in effect in the instant application:
Cis regulatory elements: d. polyadenylation sequences;
Promoters: a. ubiquitous promoter.
Claims 5-6 remain withdrawn from consideration as being directed to a nonelected species. In light of Applicant’s amendments to claim 1 such that independent claim 1 now recites “operably linked to a JeT promoter or a synapsin I (Syn1) promoter”, which are nonelected species of neuron-specific promoters, the election of species requirement for 2) promoters has been revised to include either of the two promoters now recited in claim 1. Additionally, independent claim 1 has been amended to recite that the scAAV vector comprises “one or more polyadenylation sequences”; in view of this amendment and the language of claim 3 requiring that the scAAV further comprise one or more cis-regulatory elements that increase expression of the MCOLN1, the election of 1) cis regulatory elements has been expanded to include enhancers.
Claims 1, 3-7, 9-15, and 22-26 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/US2020/057839, filed 29 October 2020, which claims priority to US. Provisional Application No. 62/927,538, filed 29 October 2019.
Thus, the earliest possible priority for the instant application is 29 October 2019.
Drawings
The objection to the drawings of the disclosure for partial views labeled “continued” is withdrawn in view of the amendment to the drawings updating the labels and the accompanying specification updating the Brief Description of the Drawings.
Specification
The objection to the specification of the disclosure for using of trade names and/or marks used in commerce without appropriate generic terms and proper symbols is maintained.
Although most of the trade names and/or marks identified in the prior action were appropriately amended in the specification amendment to insert generic terms, capitalize the term, and include appropriate symbols, use of the term “QIAZol” was not amended to be accompanied by the generic terminology, capitalized, and include the proper symbol for all instances of the term. Note that page 7 of the specification amendment filed 25 September 2025 includes a paragraph replacing the paragraph beginning at page 20, line 29 of the previously filed specification. The replacement paragraph recites the term “QIAzol” in line 2 without the generic terminology, capitalization, nor symbol.
Also note that the same paragraph on page 7 of the specification amendment filed 25 September 2025 newly comprises an apparent typographical spelling error in reciting “QUIAZOL®” in line 4 of the replacement paragraph. Appropriate correction is required.
Claim Objections
The objection to amended claim 12 for reciting “intracerebroventicular” is withdrawn in view of the amendment to claim 12 correcting the spelling error.
Claim Rejections - 35 USC § 112(b)
The rejection of amended, previously presented, original, and cancelled claims 1-4, 7-15, and 22 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:
Claim 1 recites, “An adeno-associated (scAAV) viral vector” and claims 2-3 and 7-10 each refer to “the AAV of claim 1” without the “sc”;
claim 2 recites, “The AAV of claim 1, which is a self-complementary scAAV or single-stranded AAV-PHP.b”;
claim 8 reciting the phrase "preferably" twice in line 2; and
claim 9 recites, “wherein the AAV is AAV9 serotype and comprises a JeT promoter or a Syn1 promoter and polyadenylation sequence”;
is withdrawn in view of Applicant’s amendments to the claims such that claim 1 now recites “A self-complementary adeno-associated viral (scAAV) vector, dependent claims have been amended to recite “the scAAV vector of claim 1”, and claim 9 has been amended to remove “and comprises a JeT promoter or a Syn1 promoter and polyadenylation sequence”.
**The following new rejection is necessitated by amendments to the claims.**
New and rejoined claims 25 and 26 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.
New claims 25 and 26 each recite, “wherein the scAAV vector is at least 80% identical to SEQ ID NO:”, which is indefinite because it is unclear how a vector can be identical to a sequence identifier. As such, the metes and bounds of the claim cannot be determined.
In the interest of compact prosecution, new claims 25 and 26 have been interpreted such that the scAAV vector comprises a nucleic acid sequence which is at least 80% identical to the nucleic acid sequence according to SEQ ID NO: 4 or 5, respectively.
Claim Rejections - 35 USC § 112(a)- Written Description
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.
**The following new rejection is necessitated by amendments to the claims.**
New claims 25 and 26 are newly 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. This is a new matter rejection.
The applicant is reminded that an amendment to the claims or the addition of a new claim must be supported by the description of the invention in the application as filed. In re Wright, 866 F.2d 422, 9 USPQ2d 1649 (Fed. Cir. 1989). New or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972).
New claims 25 and 26 recite wherein the scAAV vector is at least 80% identical to SEQ ID NO: 4 or 5, respectively. However, although the disclosure teaches the sequences of SEQ ID NOs: 4 and 5, the specification does not disclose sequences which are at least 80% identical to the sequences of SEQ ID NOs: 4 or 5. The specification teaches sequences encoding an MCOLN1 protein according to SEQ ID NO: 1, wherein the coding sequences is at least 80% identical to the sequence of SEQ ID NO: 2, such as codon-optimized sequences [page 11 lines 10-11]. Figures 8A and 8B provide plasmid maps for SEQ ID NO: 4 and 5, respectively, but do not present any deviations from the recited sequences themselves. However, there are no teachings in the specification for full vector plasmid sequences which deviate from the sequences taught for SEQ ID NO: 4 and 5.
To the extent that the coding sequence itself is taught to deviate up to 80%, while still encoding the sequence of SEQ ID NO: 1, such a deviation does not amount to an 80% deviation in the full sequences of SEQ ID NO: 4 or 5. As such, the disclosure does not provide support the limitations of “wherein the scAAV vector is at least 80% identical to SEQ ID NO:4” or “wherein the scAAV vector is at least 80% identical to SEQ ID NO: 5” for the scAAV vector as claimed in new claims 25 and 26, and the limitations represent new matter.
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 rejection of amended, previously presented, and cancelled claims 1, 3-4, 7-8, 10, and 13 under 35 U.S.C. 102(a)(1) as being anticipated by Goldin [US20030064363A1, published 3 April 2003], is withdrawn in view of Applicant’s claims which now recite “A self-complementary adeno-associated viral (scAAV) vector” and “operably linked to a JeT promoter or a synapsin I (Syn1) promoter” in claim 1.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, original, and cancelled claims 1-4, 7-15, and 22 under 35 U.S.C. 103 as being unpatentable over Goldin (US20030064363A1, published 3 April 2003); in view of Hudry & Vandenberghe (2019, Neuron, 101, 839-862, published 6 March 2019); Bailey et al. (2018, Molecular Therapy: Methods & Clinical Development, 9, 160-171, S1-S8), IDS; and Grimm & Cuajungco (2014, Pathologies of Calcium Channels, Chapter 19: TRPML Channels and Mucolipidosis Type IV, 365-379); is withdrawn over cancelled claims 2 and 8, maintained over amended, previously presented, and original claims 1, 3-4, 7, 9-15, and 22, and newly applied to new claim 23. 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 recite an scAAV vector, that the scAAV vector comprises one or more polyadenylation sequences, and that the sequence encoding MCOLN1 protein is operably linked to a JeT promoter or a Syn1 promoter. New claim 23 recites specifically the use of the JeT promoter.
However, each of these limitations were previously recited in claims 2, 8, and/or 9 and addressed in the prior action. Goldin was cited for teaching that the polynucleotides be flanked by regulatory expression control sequences including promoters and polyadenylation sequences [0044]. Hudry was cited for teaching that packaging of self-complementary genomes has allowed successful and substantial CNS transduction following systemic administration of AAV9 [column 13 ¶ 3]. Therefore, and ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a single-stranded AAV-PHP.B serotyped AAV vector or a self-complementary AAV9 (scAAV9) serotyped AAV vector for successful and substantial gene delivery to the central nervous system.
Bailey was cited for teaching the use of an scAAV9 vector carrying a GAN transgene whose expression is controlled by the minimal synthetic JeT promoter (AAV9/JeT-GAN), wherein delivery of the vector in GAN KO mice sustained levels of human GAN expression for at least 1 year and resulted in accompanying symptom improvements [column 3 ¶ 1-2]. Bailey also teaches that given AAV packaging constraints, the short JeT promoter allows sc packaging of the 1.9 kb GAN coding sequence, which is predicted to stably transduce at least 10-fold more cells than single-stranded (ss) AAV [column 3 ¶ 2]. Baily also teaches, that in their system, use of the weak JeT promoter was equally beneficial as using the stronger CMV promoter [column 5 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to substitute the CMV promoter, as taught by Goldin, with a JeT promoter to reduce the size of the promoter sequence, and thereby allow insertion of a larger gene into an AAV vector, particularly an scAAV vector which has smaller packaging limits, while preserving beneficial expression levels of the transgene.
Additionally, Applicant’s incorporation of a requirement for the scAAV vector to comprise one or more polyadenylation sequences in amended claim 1 now changes the scope of claims 3-4 to require one or more cis-regulatory elements that increase expression of the MCOLN1 in addition to the polyadenylation sequence. Accordingly, the election of species for cis regulatory elements has been expanded to include enhancers. The amendment does not overcome a finding of obviousness over the cited references in that Goldin teaches that the polynucleotides comprise expression control sequences including enhancers [0044, 0046, 0083].
Accordingly, Applicants amendments to the claims do not overcome a finding of obviousness over Goldin, Hudry, Bailey, and Grimm under 35 USC 103.
Applicant argues that:
nothing in Goldin or Grimm provides any motivation to modify a viral vector encoding MCOLN1 protein to be particularly well suited for administration to the central nervous system by specifically using an scAAV or by selecting a JeT or Syn promoter; and
the skilled artisan would have had no reasonable expectation of success in achieving the claimed invention because
a skilled artisan would have had no reasonable expectation that the MCOLN1 encoding vectors of Goldin could be combined with the scAAV of Hudry along with the JeT promoter of Bailey to successfully arrive at a scAAV vector as claimed;
nothing in Goldin or Grimm provides any evidence or experimental results that suggest that a gene therapy would actually be successful in the treatment of mucolipidosis IV such that nothing in any of the cited references would provide one skilled in the art with any reasonable expectation that administration of an scAAV vector having a sequence encoding MCOLN1 protein, operably linked to a JeT promoter or a Syn1 promoter, and one or more polyadenylation sequences would be successful in treating symptoms of mucolipidosis IV.
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), that nothing in Goldin or Grimm provides any motivation to modify a viral vector encoding MCOLN1 protein to be particularly well suited for administration to the central nervous system by specifically using an scAAV or by selecting a JeT or Syn promoter; note that Goldin and Grimm were not relied on for specifically teaching administration to the central nervous system nor for using an scAAV or JeT promoter.
Additionally, Goldin was cited for teaching that the symptoms of mucolipidosis include psychomotor retardation such that most patients are unable to speak or walk independently, corneal clouding and progressive retinopathy with optic atrophy resulting in severe visual impairment, and a decline in motor function [0005]. Goldin further teaches that mucolipidosis IV (MLIV) in autosomal recessive developmental neurological disorder characterized by severe neurologic and ophthalmic abnormalities, including abnormal brain, eye, and gastric functions [0004, 0020], and that some patients exhibit neurological deterioration [0005]. Goldin further teaches that treatment of mucolipidosis involves transferring a vector comprising a gene for a functional MCOLN1 into target cells of a subject suffering from mucolipidosis, i.e., cells in which MCOLN1 expression has been observed, and in which MCOLN1 mutations results in defects, including neuronal and gastric cells [0167]. Goldin additionally teaches that MCOLN1 encodes mucolipin, and that mucolipin may play a major role in the development of white matter tracts and in the maintenance of neurons and retinal cell integrity, as suggested by the pathology and neuro-imaging studies of MLIV patients [0008, 0199]. Goldin also teaches that MLIV will be a useful model in which to study the role of a distinct ion channel gene in brain development and neuronal maintenance [0201]. Taken together, Goldin teaches a significant role for MCOLN1 in the central nervous system (e.g., brain) and further teaches to deliver the MCOLN1 rAAV vector to affected cells including neuronal cells, thereby providing strong motivation to administer an rAAV vector encoding MCOLN1 to cells of the central nervous system.
Hudry was cited for providing the teachings and motivation for using scAAV for the particular administration to central nervous system cells. Hudry was cited for teaching that the vector of choice for many nervous system targets currently is the adeno-associated viral (AAV) vector due to its desirable safety profile and strong neuronal tropism [abstract]. Hudry additionally teaches the delivery to the cerebrospinal fluid (CSF) allows for more widespread gene transfer throughout the brain and spinal cord while limiting systemic biodistribution, and that the presence of tight junctions between ependymal cells restricts such application to certain AAV serotypes, including AAV9 and PHP.B [column 11 ¶ 2]. Hudry further teaches that packaging of self-complementary genomes has allowed successful and substantial CNS transduction following systemic administration of AAV9 [column 13 ¶ 3]. Therefore, and ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a self-complementary AAV9 (scAAV9) serotyped AAV vector for successful and substantial gene delivery to the central nervous system.
Further, Bailey was cited for providing the teachings and motivation to use a JeT promoter in an scAAV vector. As discussed above, Bailey was cited for teaching the use of an scAAV9 vector carrying a GAN transgene whose expression is controlled by the minimal synthetic JeT promoter (AAV9/JeT-GAN), wherein delivery of the vector in GAN KO mice sustained levels of human GAN expression for at least 1 year and resulted in accompanying symptom improvements [column 3 ¶ 1-2]. Bailey also teaches that given AAV packaging constraints, the short JeT promoter allows sc packaging of the 1.9 kb GAN coding sequence, which is predicted to stably transduce at least 10-fold more cells than single-stranded (ss) AAV [column 3 ¶ 2]. Baily also teaches, that in their system, use of the weak JeT promoter was equally beneficial as using the stronger CMV promoter [column 5 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to substitute the CMV promoter, as taught by Goldin, with a JeT promoter to reduce the size of the promoter sequence, and thereby allow insertion of a larger gene into an AAV vector, particularly an scAAV vector which has smaller packaging limits, while preserving beneficial expression levels of the transgene.
Regarding Applicant’s argument 2)a, that the skilled artisan would have had no reasonable expectation that the MCOLN1 encoding vectors of Goldin could be combined with the scAAV of Hudry along with the JeT promoter of Bailey to successfully arrive at a scAAV vector as claimed; note that Bailey teaches the use of a JeT promoter in an scAAV [column 3 ¶ 1-2]. Regarding the feasibility of combining an MCOLN1 encoding sequence as taught by Goldin with an scAAV having the JeT promoter, note that viral vector construction is a routine process. Additionally, Hudry teaches that the capacity of AAV to package an ITR-flanked genome productively is the approximate size of the wild-type AAV genome (e.g., 4.7 kb), and that attempts to package larger genomes consistently lead to low titers and genome fragmentation [column 4 ¶ 3- column 5 ¶ 1]. Goldin teaches that the MCOLN1 is a 580 amino acid protein [0019, Figure 4a], which therefore is encoded by 1740 nucleic acids. Goldin also teaches that the full length endogenous MCOLN1 mRNA (with 5’ UTR, 3’UTR, and polyA tail) is 2.1 kb [0017-0019, Figures 2a, 2d, 3]. Bailey teaches that the short minimal synthetic JeT promoter allows sc packaging of the 1.9 kb gigaxonin coding sequence along with a synthetic polyadenylation sequence, such that the JeT promoter, coding sequence, and polyA tail all fit between the ITRs in the AAV vector genome [column 3 ¶ 2, Figure 1]. Therefore, and ordinarily skilled artisan would not find it unreasonable to combine a 1.7 kb coding sequence for MCOLN1 with a JeT promoter and a polyA sequence into an scAAV vector. Accordingly, Goldin, Hudry, and Bailey teach a reasonable expectation of success for combining MCOLN1 encoding vectors of Goldin with the scAAV of Hudry along with the JeT promoter of Bailey to successfully arrive at a scAAV vector as claimed.
Regarding Applicant’s argument 2)b, that nothing in any of the cited references would provide one skilled in the art with any reasonable expectation that administration of an scAAV vector having a sequence encoding MCOLN1 protein, operably linked to a JeT promoter, and one or more polyadenylation sequences would be successful in treating symptoms of mucolipidosis IV, note that Goldin was cited for teaching a method of treating mucolipidosis IV (MLIV) in a subject, the method comprising administering to the subject a therapeutically effective amount of the AAV comprising a sequence encoding MCOLN1 operably linked to a promoter that drives expression of the MCOLN1 protein in a cell [0008, 0012, 0079, 0083-0085, 0087, 0094-0095, 0167, 0169, claim 29]. Goldin also teaches that the invention represents a significant step forward in treating mucolipidosis [0007], to administer to a subject suffering from mucolipidosis [0167-0168], and that the symptoms of mucolipidosis include psychomotor retardation such that most patients are unable to speak or walk independently, corneal clouding and progressive retinopathy with optic atrophy resulting in severe visual impairment, and a decline in motor function [0005]. Goldin also teaches that delivery of an MCOLN1 gene therapy is particularly useful for treatment of MLIV [0168].
Additionally, Grimm was cited for teaching that gene therapy may represent an alternative approach for the treatment of MLIV mutations which result in complete loss of the TRPML1 protein/ MCOLN1 protein, as it has the potential to theoretically provide a permanent source of the deficient protein, either by direct injection of vectors or by transplantation of gene-corrected cells [page 371 ¶ 4]. Grimm also teaches that a gene therapy approach restricted, e.g., to the retina, is something that has been successfully done with other ion channels and thus may well be a promising approach to treat retinal degeneration in MLIV patients effectively [page 371 ¶ 4-page 372 ¶ 1]. Additionally, Hudry teaches that AAV gene therapies for neurological disease have been somewhat spared from major inflammatory adversity, likely due to the immune privilege that many of the compartments in the nervous system benefit from, such as brain, spinal cord, eye, and cochlea, which have limited access to circulating antibodies or infiltrating immune cells [column 16 ¶ 4]. Further, Hudry teaches that Intraparenchymal CNS or subretinal injections even have less exposure to neutralizing antibodies and likely are not affected, even if the host is highly serologically positive or has previously received an AAV injection (e.g., when administering a retinal gene therapy in both eyes) [column 16 ¶ 4]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to inject a gene therapy AAV construct expressing MCOLN1 into the CNS of a subject having mucolipidosis Type IV to effectively treat mucolipidosis, effectively transduce neuronal cells of the CNS, and minimize inflammatory adversity.
Additionally, Bailey teaches the intrathecal (IT) administration of a gene therapy construct to treat a neurodegenerative disorder, such that IT-delivered AAV9 can transduce the majority of motor neurons in the spinal cord and the neurons of the dorsal root ganglia (DRG) with minimal targeting of virus to peripheral organs as compared to systemic delivery [column 2 ¶ 2], wherein delivery of the vector expressing human GAN in GAN KO mice sustained levels of human GAN expression for at least 1 year and resulted in accompanying symptom improvements [column 3 ¶ 1-2]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to deliver a gene therapy construct for treating a neurodegenerative disease by administering into the CNS by intrathecal injection to allow for transduction of CNS neurons with minimal targeting of virus to peripheral organs.
Given the teachings of Goldin that the vectors express functional human MCOLN1 in human target cells and a method of treating mucolipidosis by administering the vector into cells of the subject [0012]; the teachings of Grimm that gene therapy may represent an alternative approach for the treatment of MLIV mutations which result in complete loss of the TRPML1 protein/ MCOLN1 protein, as it has the potential to theoretically provide a permanent source of the deficient protein, either by direct injection of vectors or by transplantation of gene-corrected cells [page 371 ¶ 4]; and the teachings of Bailey of the successful expression of scAAV transduced neuronal cells, including the intrathecal (IT) administration of a gene therapy construct to treat a neurodegenerative disorder, such that IT-delivered AAV9 can transduce the majority of motor neurons in the spinal cord and the neurons of the dorsal root ganglia (DRG) with minimal targeting of virus to peripheral organs as compared to systemic delivery, wherein delivery of the vector sustained levels of expression for at least 1 year and resulted in accompanying symptom improvements [column 2 ¶ 2, column 3 ¶ 1-2]; an ordinarily skilled artisan at the time of filing the instant application would have had a reasonable expectation of success for a) administering a MCOLN1 scAAV vector to the CNS of human, b) achieving expression of the encoded MCOLN1 protein from the administered scAAV vector, and c) achieving an improvement in at least one or more symptom of mucolipidosis.
Therefore, Applicant’s arguments do not overcome a finding of obviousness over Goldin, Hudry, Bailey, and Grimm under 35 USC 103, and the rejection is maintained.
**The following new rejection is necessitated by Applicant’s amendments to the claims.**
New claims 24-26 are newly rejected under 35 U.S.C. 103 as being unpatentable over Goldin [US20030064363A1, published 3 April 2003, cited in a prior action]; in view of Hudry & Vandenberghe [2019, Neuron, 101, 839-862, published 6 March 2019, cited in a prior action]; Bailey et al. [2018, Molecular Therapy: Methods & Clinical Development, 9, 160-171, S1-S8, IDS, cited in a prior action]; and Grimm & Cuajungco [2014, Pathologies of Calcium Channels, Chapter 19: TRPML Channels and Mucolipidosis Type IV, 365-379, cited in a prior action]; as applied to amended, previously presented, original, rejoined, and new claims 1, 3-4, 7, 9-15, and 22-23 above; and further in view of Lukashchuk et al. [2016, Molecular Therapy Advances, 3, 15055, 1-10]; Chew et al. [2016, Nature Methods, 13(10), 868-874]; Addgene [2025, retrieved on 18 December 2025 from:< https://www.addgene.org/search/by-sequence/?sequence_type=nucleotide&algorithm=megablast&db=all&sequence_id=ceb26ac4acbd58379c3faf57a2a872ed&max_results=25>, herein referred to as “Addgene1”]; Addgene [2017, pAAV-CASI-Cas9C-P2A-turboGFP (Plasmid #80942), retrieved on 18 December 2025 from: <https://web.archive.org/web/20170506181441/https://www.addgene.org/80942/>, archived on 06 May 2017, herein referred to as “Addgene2”]; Tornoe et al. [2002, Gene, 297, 21-32, IDS]; Addgene [2025, Sequence Analyzer: pAAV-hSyn-RFP (Plasmid #22907) Sequencing Result #129530, retrieved on 18 December 2025 from: <https://www.addgene.org/browse/sequence/129530/>, herein referred to as “Addgene3”]; and Swiech et al. [2014, Nature Biotechnology, 33(1), 102-106].
As discussed above, Goldin, Hudry, Bailey, and Grimm teach an scAAV vector comprising as sequence encoding MCOLN1 protein, operably linked to a JeT promoter that drives expression of the MCOLN1 protein in a cell, and one or more polyadenylation sequences, as recited in amended independent claim 1.
Regarding new claim 24, Goldin, Hudry, Bailey, and Grim do not teach to use the Syn1 promoter.
However, Lukashchuk teaches that several studies have shown efficient neuronal targeting using a short ~400 bp SYN1 promoter sequence [column 3 ¶ 3], and confirmed the neuronal tropism of the SYN1 promoter in an scAAV vector [column 3 ¶ 3-column 4 ¶ 2, Figure 1]. Lukashchuk also teaches that direct administration of scAAV9 to the CSF, coupled with the use of a specific promoter, can further target desired cell types within the CNS and is of particular interest to neurodegeneration therapeutics, where cell-specific expression of a transgene may be required [column 10 ¶ 2]. Lukashchuk teaches that widespread gene delivery throughout the brain and spinal cord by delivering scAAV-GFP into cisterna magna of neonatal mice, wherein the SYN1 promoter offered a uniform neuron-specific transduction throughout the CNS, including efficient gene transfer in the brain and spinal cord of young mice, covering cerebellum, brain stem, hippocampus, and cortices [column 10 ¶ 2]. Lukashchuk further teaches that when there is a risk of disseminated expression of a protein with a potentially toxic function in off-target cell types and organs, neuron-specific promoters are preferred, and that the SYN1 promoter may provide such utility for the AAV0-mediated therapy targeting neurological diseases, as it confers minimal non-neuronal gene expression when used with scAAV9 background [column 10 ¶ 4- column 11 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a SYN1 promoter in an scAAV9 vector for gene therapy targeting neuronal cells to achieve efficient gene transfer in the brain and spinal cord with minimal non-neuronal gene expression.
Regarding claims 25 and 26, Goldin, Hudry, Bailey, Grimm, and Lukashchuk do not explicitly recite a sequence which is at least 80% identical to SEQ ID NOs: 4 or 5. Note that instant SEQ ID NOs: 4 and 5 are identical to each other across the ranges of 1-116 and 312-5158 (of SEQ ID NO: 4) and 1-116 and 565-5411 (of SEQ ID NO: 5), respectively, such that the difference between the two sequences corresponds to inclusion of different promoter sequences, wherein SEQ ID NO: 4 comprises a JeT promoter and SEQ ID NO: 5 comprises a SYN1 promoter.
However, Chew teaches plasmids used to produce AAV9-Cas9C-P2A-turboGFP virus and AAV9-Cas9C virus, which are available through Addgene (IDs 80930-80944); that the AAV plasmid backbone was derived from pZac2.1-CASI-EGFP-RGB; and that the plasmids were used to successfully produce AAV virus which successfully transduced target cells [column 3 ¶ 1, column 1 ¶ 3, column 15 ¶ 1, column 17 ¶ 9, column 19 ¶ 3, 5, Figure S2, supplementary sequence page 2]. Addgene1 teaches plasmid 80942 (e.g., pAAV-CASI-Cas9C-P2A-turboGFP) comprises sequences which are 100% matches to nucleotides 2143-5157 and 0-105 of instant SEQ ID NO: 4, which are nucleotides 1-106 and 2144-5158 according to the numbering of SEQ ID NO:4 wherein the first nucleotide is numbered “1” instead of “0” (e.g., nucleotides 4578-7592 and 0-105 of pAAV-CASI-Cas9C-P2A-turboGFP) [page 2-6]. Addgene1 teaches plasmid 80932 (e.g., pAAV-CASI-Cas9C) comprises sequences which are 100% matches to nucleotides 2143-5157 and 0-105 of instant SEQ ID NO: 4 (e.g., nucleotides 3834-6848 and 0-105 of pAAV-CASI-Cas9C) [page 7-12]. Addgene1 also teaches that these nucleotides correspond to common plasmid backbone sequences comprising an AAV2 inverted terminal repeat (ITR), f1 ori, AmpR, ori, and another AAV2 ITR [page 1 plasmid map and page 7 plasmid map], thereby comprising all of the plasmid vector sequences from the 3’ ITR to the 5’ ITR with 100% identity, which amounts to the complete vector backbone without the inserted promoter-transgene-polyA sequences.
Although the Addgene1 teachings rely on a sequence search and alignment generated on 18 December 2025, the reference relies on information from plasmid information deposited prior to publication of the Chew paper in 2016, and made public at least by 06 May 2017, as taught by Addgene2. Note that reliance upon inherency is not improper even though rejection is based on Section 103 instead of Section 102. In re Skoner, et al. 186 USPQ 80 (CCPA). As stated in MPEP 2112, The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. "The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness." In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995). See also In re Grasselli, 713 F.2d 731,739, 218 USPQ 769, 775 (Fed. Cir. 1983). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Regarding the MCOLN1 coding sequence, Goldin teaches the MCOLN1 cDNA sequence (e.g., SEQ ID NO: 2) which comprises a sequence which is 99.8% identical to nucleotides 325-2075 of instant SEQ ID NO: 4 [0069], wherein the aligning sequence comprises the full coding sequence (start codon through stop codon):
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948
575
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783
578
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Therefore, Goldin teaches an MCOLN1 coding sequence which is 100% identical to the MCOLN1 coding sequence included in instant SEQ ID NOs: 4 and 5.
Regarding the JeT promoter sequence, Bailey teaches that the JeT promoter used was a minimal synthetic JeT promoter from reference 25, Tornoe et al. 2002 [column 15 ¶ 2]. Tornoe teaches the sequence for the minimal synthetic JeT promoter in Figure 1, which is a 100% sequence match for nucleotides 117-311 of instant SEQ ID NO: 4:
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351
641
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Therefore, the JeT promoter taught by Bailey is 100% identical to the JeT promoter included in instant SEQ ID NO: 4.
Regarding the Syn1 promoter sequence, Lukashchuk teaches that the human synapsin 1 promoter was amplified from pAAV-SYN1-RFP which was deposited to Addgene as plasmid #22907 [column 11 ¶ 2]. Addgene3 teaches that the pAAV-SYN1-RFP plasmid has a SYN1 promoter encompassing nucleotides 223-670, which are a 100% match to nucleotides 117-564 of instant SEQ ID NO: 5:
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638
646
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Therefore, the Syn1 promoter taught by Lukashchuk is 100% identical to the Syn1 promoter included in instant SEQ ID NO: 5.
Regarding the polyA sequence, Bailey teaches the use of a synthetic polyA tail (SpA) in the scAAV comprising the JeT promoter and an SV40 polyA tail in another scAAV [Figure S1]. Swiech teaches that they assessed various polyadenylation signals to achieve efficient packaging of a SpCas9 transgene in AAV vectors, and chose to use a minimal 48 bp synthetic polyadenylation signal (spA) to minimize the SpCas9 expression cassette size [column 1 ¶ 2, Figure 1, 4, S1]. Swiech teaches the sequence for the spA polyadenylation signal, wherein the oligos used to clone the spA into the construct comprise a 50 nt sequence which is 100% identity match to nucleotides 2082-2131 of instant SEQ ID NO: 4 [column 11 ¶ 3]:
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136
638
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Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use a minimal SpA polyadenylation sequence to minimize the size of an expression cassette for packaging into an AAV viral vector.
Accordingly, regarding SEQ ID NO: 4, Chew teaches a vector backbone which is 100% identical to nucleotides 1-106 (106 nt) and 2144-5158 (3015 nt), Bailey and Tornoe teach a JeT promoter which is 100% identical to nucleotides 117-311 (195 nt), Goldin teaches an MCOLN1 coding sequence with is 99.8% identical to nucleotides 325-2075 (1751 nt * 99.8% = 1747 nt)), and Bailey and Swiech teach a polyA signal which is 100% identical to nucleotides 2082-2131 (50 nt) of instant SEQ ID NO: 4. Therefore, the combination of references specifically teach 5113 nt out of the 5158 nucleotides of SEQ ID NO: 4, which corresponds to 99.1% of the sequence according to instant SEQ ID NO: 4. Therefore, by teaching to include such sequences, Goldin, Hudry, Bailey, Grimm, Chew, Lukashchuk, Tornoe, Swiech, Addgene1, Addgene2, and Addgene3 are teaching an AAV viral vector which has at least 99.1% identity to the sequence according to instant SEQ ID NO: 4.
Regarding SEQ ID NO: 5, Chew teaches a vector backbone which is 100% identical to nucleotides 1-106 (106 nt) and 2397-5411 (3015 nt), Lukashchuk and Addgene3 teach a SYN1 promoter which is 100% identical to nucleotides 117-564 (448 nt), Goldin teaches an MCOLN1 coding sequence with is 99.8% identical to nucleotides 578-2328 (1751 nt * 99.8% = 1747 nt)), and Bailey and Swiech teach a polyA signal which is 100% identical to nucleotides 2335-2384 (50 nt) of instant SEQ ID NO: 5. Therefore, the combination of references specifically teach 5260 nt out of the 5411 nucleotides of SEQ ID NO: 5, which corresponds to 99.2% of the sequence according to instant SEQ ID NO: 5. Therefore, by teaching to include such sequences, Goldin, Hudry, Bailey, Grimm, Chew, Lukashchuk, Tornoe, Swiech, Addgene1, Addgene2, and Addgene3 are teaching an AAV viral vector which has at least 99.1% identity to the sequence according to instant SEQ ID NO: 5.
Given the teachings and motivation of Lukashchuk to use a SYN1 promoter in an scAAV9 vector for gene therapy targeting neuronal cells to achieve efficient gene transfer in the brain and spinal cord with minimal non-neuronal gene expression; the teachings of Chew and Addgene1 of a plasmid sequence comprising a nucleotides sequences with 100% identity to nucleotides that the sequence corresponding to nucleotides 1-106 & 2144-5158 of instant SEQ ID NO: 4 and nucleotides 1-106 & 2396-5411 of instant SEQ ID NO: 5, wherein such sequences represent common plasmid backbone sequences; the teachings of Bailey and Tornoe of a JeT promoter which is 100% identical to nucleotides 117-311 of instant SEQ ID NO: 4; the teachings of Lukashchuk and Addgene3 of a SYN1 promoter which is 100% identical to nucleotides 117-564 of instant SEQ ID NO: 4; and the teachings of Bailey and Swiech of a polyA signal which is 100% identical to nucleotides 2082-2131 of instant SEQ ID NO: 4 and nucleotides 2335-2384 of instant SEQ ID NO: 5; it would have been prima facie obvious to an ordinarily skilled artisan to combine the scAAV vector encoding MCOLN1 of Goldin with the vector backbone, JeT promoter of Bailey and Tornoe, SYN1 promoter of Lukashchuk and Addgene3, and the polyA signal of Bailey and Swiech to arrive at scAAV vector plasmid sequences which are at least 80% (e.g., 99%) identical to instant SEQ ID NO: 4 or 5 with a reasonable expectation of success.
Double Patenting
The rejection of amended and cancelled claims 1-4 and 7-9 on the ground of nonstatutory double patenting as being unpatentable over 1-46 of U.S. Patent No. 7,041,448, hereafter referred to as the ‘448 patent, in view of Hudry & Vandenberghe (2019, Neuron, 101, 839-862, published 6 March 2019); and Bailey et al. (2018, Molecular Therapy: Methods & Clinical Development, 9, 160-171, S1-S8), IDS ; is withdrawn over cancelled claims 2 and 8, maintained over amended claims 1, 3-4, 7, and 9, and newly applied to new claims 23-26.
The Applicant requests that the rejection be held in abeyance until the indication of allowable subject matter. However, the instant rejection may not be held in abeyance. As set forth in MPEP 804, only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. A complete response to a nonstatutory double patenting (NDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (MPEP 804 (B)(1)). Such a response is required even when the nonstatutory double patenting rejection is provisional.
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