Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Action is in response to the papers filed on December 22, 2025 for a Request for Continued Examination. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 22, 2025 has been entered.
Claims 1, 2, 4, 6, 7, 11-15, and 58, 60, 62-69 are currently pending. Claims 1, 4, and 58 have been amended, claims 59 and 61 have been cancelled, and claims 67-69 are newly added in Applicant’s amendment filed October 22, 2025.
Therefore, claims 1, 2, 4, 6, 7, 11-15, and 58, 60, 62-69 are currently under examination to which the following grounds of rejection are applicable.
Response to Arguments
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4, 6, 7, 11-15, and 58, 60, 62-66 remain and claims 67-69 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 claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that
the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP § 2163. The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
Claim 1 is directed a composition comprising a recombinant adeno-associated virus (AAV), the recombinant AAV comprising: (a) an AAV capsid; and (b) a vector genome comprising (i) a galactosylceramidase coding sequence operably linked to regulatory sequences, wherein the galactosylceramidase coding sequence comprises nucleotides 1 to 2055 of SEQ ID NO: 9 or a sequence 95 to 99.9% identical to nucleotides 1 to 2055 of SEO ID NO: 9 that encodes amino acids 1 to 685 of SEO ID NO: 10; and (ii) AAV inverted terminal repeats necessary for packaging the vector genome in the AAV capsid, wherein the vector genome is packaged in the AAV capsid.
Claim 58 is directed to a composition comprising a recombinant adeno-associated virus (AAV), said recombinant AAV comprising an AAVhu68 capsid having packaged therein a vector genome comprising:
(a) a 5' AAV ITR sequence;
(b) a promoter sequence;
(c) an intron sequence;
(d) a galactosylceramidase coding sequence comprising nucleotides 1 to 2055 of SEQ ID NO: 9 or a sequence 95 to 99.9% identical to nucleotides 1 to 2055 of SEO ID NO: 9 that encodes amino acids 1 to 685 of SEQ ID NO: 10, wherein the galactosylceramidase coding sequence is operably linked to the promoter sequence.
(e) a polyA sequence; and
(f) a 3' AAV ITR sequence.
In analyzing whether the written description requirement is met, it is first determined whether a representative number of species have been described by their complete structure. Next, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics. Claims 1 and 58 are broadly directed to a composition comprising a recombinant adeno-associated virus (AAV) comprising a galactosylceramidase coding sequence comprising nucleotides 1 to 2055 of SEQ ID NO: 9 or a sequence at least 95% identical thereto that encodes amino acids 1 to 685 of SEQ ID NO: 10; however, the Specification only supports the full SEQ ID NO:9 as opposed to the claimed threshold of “at least 95%”.
The Remarks filed on March 30, 2025, state that the prior art rejections would not be obvious due to degeneracy of the genetic code that would lead to a large number of sequence options to encode for the same wild-type amino acid sequence. Applicant states, “Indeed, SEQ ID NO: 9 is less than 76% identical to the native human GALC coding sequence (provided in SEQ ID NO:5). Due to the degeneracy of the genetic code, an extraordinarily large number of sequences ( over 10206 sequences1) are predicted to encode a GALC protein having 685 amino acid residues. The selection of the coding sequence of SEQ ID NO: 9, or a sequence at least 99% identical to SEQ ID NO: 9, is not obvious.” Therefore, to rely on this argument, the SEQ ID NO: 9 comprised in the claimed recombinant AAV vector should be at least 99% identical because the GALC amino acid sequence as seen in SEQ ID NO: 10 is well-known, yet the specific optimized coding sequence was not.
Teachings within the Specification:
The Background of the Invention overviews Krabbe disease and the cause related to mutations in the gene encoding the hydrolytic enzyme galactosylceramidase (GALC). The section further describes the role of the enzyme, and current therapies available for patients with such disease, primarily therapies using hematopoietic stem cell transplants (HSCT).
The Summary of the Invention states the composition comprises an rAAV having the vector genome CB7.CI.hGALC.rBG. Figure 2 depicts the employed vector genome, “FIG. 2 shows a schematic of the CB7.CI.hGALC.rBG vector genome. The linear map depicts the vector genome, which is designed to express human GALC under the control of the ubiquitous CB7 promoter. CB7 is composed of hybrid between a CMV IE enhancer and a chicken J3-actin (CB) promoter. Abbreviations: CMV IE, cytomegalovirus immediate-early; GALC, galctosylceramidase; ITR, inverted terminal repeats; PolyA, polyadenylation; rBG, rabbit J3-globin. The GALC sequences is described as the human GALC sequence; and is further described as comprising SEQ ID NO. 9 on page 58, lines 18-22.
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Under the Detailed Description of the Invention, it is stated “In certain embodiments, the CB7.CI.hGALC.rBG includes a coding sequence for GALC that contains the nucleic acid sequence of SEQ ID NO: 9 or a sequence 95% to 99.9% identical thereto. In yet another embodiment, the CB7.CI.hGALC.rBG vector genome includes SEQ ID NO: 19. In certain embodiments, the CB7.CI.hGALC.rBG contains a coding sequence for the mature protein of SEQ ID NO: 10 and an exogenous signal peptide.” SEQ ID NO: 19 is 4386 nt in length of which SEQ ID NO: 9 (2055 nt) is comprised at locations 1948-4002.
The section further states that nucleic acid sequences which encode the GALC protein(s) provided herein (e.g., SEQ ID NO: 6, SEQ ID NO: 10, or fusion proteins comprising the mature GALC) are encompassed by the invention.
“In particular, the present disclosure provides rAAV comprising a coding sequence of human galactosylceramidase (GALC). In some embodiments, the coding sequence is an engineered GALC coding sequence.” (p 32, lines 17-20). This section further reveals the sequence of SEQ ID NO: 9 is engineered or rather codon optimized as supported by the Remarks filed on March 30, 2025 and on page 20, “Such nucleic acid sequences may be codon-optimized for expression in a selected system (i.e., cell type) can be designed by various methods. This optimization may be performed using methods which are available on-line (e.g., GeneArt), published methods, or a company which provides codon optimizing services, e.g., DNA2.0 (Menlo Park, CA)... A number of options are available for performing the actual changes to the codons or for synthesizing the codon-optimized coding regions designed as described herein. Such modifications or synthesis can be performed using standard and routine molecular biological manipulations well known to those of ordinary skill in the art”.
The Specification in combination with the drawing only support SEQ ID NO: 9 and 19 for which they employ encode the same codon-optimized GALC sequence. In reference to the specific codons that are to be optimized or left alone are not specifically stated in the disclosure, and this is important as the Remarks states it would not be obvious to optimize the codons to arrive at the same sequence of claimed invention despite the Specification clearly describing the tools for doing so being well-known in the art. Altogether, the claimed composition are only supported at the full lengths of SEQ ID NO: 9.
Working Examples:
The Specification includes 6 Examples of which Example 1 is directed to the recombinant AAVhu68.hGALC vector that is depicted in Fig. 2 which appears to be the SEQ ID NO: 19. Section A explains the GALC sequence comprised in the vector, “Coding sequence: An engineered cDNA of the human GALC gene encodes human galactosylceramidase protein, which is a lysosomal enzyme responsible for the hydrolysis and degradation of myelin galactolipids (2055 hp; 685 amino acids [aa], GenBank: EAW81361.l).”
Example 2 looks at delivery of AVhu68.hGALC in the GALC-deficient twitcher mouse model wherein it states, “The studies described below used the Twitcher mouse model to establish the potential for delivery of an rAAVhu68 vector (FIG. 2) encoding an engineered human GALC sequence (SEQ ID NO: 9) into the CSF to achieve therapeutic levels of GALC expression levels and rescue several biomarkers of the disease.” ( p 58, lines 18-22).
Example 3 employs the same vectors as Examples 1 and 2, and investigates the minimum effective dose of the vector in the Twitcher mouse model. The same vector was used in Example 5 for rhesus macaques and in Example 6 for human clinical trials. Example 4 employed a different viral vector wherein the coding sequences for GALC was a canine codon optimized sequence. As a whole, in terms of using a human GALC sequence as stated in claims 1 and claim 58 (based on identity to SEQ ID NO: 10), the vectors only use the full lengths of SEQ ID NO: 9.
Prior Art:
As stated in the rejection below, Escolar et al. (US-2019/0336540-A1; of record) teaches the treatment of Krabbe disease by gene therapy, wherein the treated subject can have any form of Krabbe disease, such as early infantile Krabbe disease, late infantile Krabbe disease, or juvenile Krabbe disease (par 0005, 0074). The vector includes a full-length human galactosylceramidase (GALC) cDNA (par 0107; figure 1). The GALC sequences employed are the nucleic acid sequence of SEQ ID No: 1 and the protein sequence of SEQ ID No: 2 (p.4 lines 25-26).
The human GALC protein sequence of Escolar SEQ ID No: 2 is different from SEQ ID No: 10 of the instant application by 1 a.a. (position 641 of SEQ ID No: 10, alignment provided below in Figure 1). However, Escolar teaches other sequences, including Genbank Accession Number. AAH36518.1 (par 0031) which comprises a signal peptide (par 0103), which remains different by 1 a.a. to a.a. 43-685 of instant SEQ ID No: 10, but in a different region than shown in the prior alignment (alignment provided below in Figure 3).
In reference to SEQ ID NO: 9 (2055 nt) the closest sequence similarity was around 90%, which is outside the claimed similarity window (alignment provided in the Office Action dated September 30, 2024 under the name “STIC_Search_SEQIDNOS9”; screenshot provided below in Fig. 4). The first two matches with the highest alignments scores were the inventors’ reference(s), followed by the third alignment being of GALC RNA that has 89.8% similarity, and the fourth alignment having a 87.7% similarity. The fourth alignment is from Prevail Ther. (WO2019070894) in which the compared sequence, SEQ ID NO: 34, is described as “Gcase protein flanked by two adeno-associated virus (AAV) inverted terminal repeats (ITRs), where one of the ITRs comprises a modified 'D' region relative to a wild-type AAV2 ITR sequence.”
In summary, the art shows that the full sequence of the human GALC gene is well-known in the art, yet the specific codon optimized sequence of SEQ ID NO: 9 was not known in the art. The purpose of maintaining the obviousness rejection is that the encoded amino acid sequence which provides the therapeutic effects is known in the art, and additionally, optimization techniques being also known, and therefore it would be obvious to optimize the coding sequence to improve therapeutic outcomes when administering the claimed vector.
Conclusion:
The disclosure does not support the scope encompassed by a composition comprising a recombinant adeno-associated virus (AAV) comprising a galactosylceramidase coding sequence comprising a sequence at least 95% identical to SEQ ID NO: 9 that encodes amino acids 1 to 685 of SEQ ID NO: 10; however, the Specification only supports the full length of SEQ ID NO:9 as opposed to the claimed threshold of “95-99.9% identical.”
Response to Applicants' Arguments as they apply to rejection of claims 1, 2, 4, 6, 7, 11-15, and 58-66 rejected under 35 USC § 112(a):
Starting on page 6 of the remarks filed on October 22, 2025, Applicants essentially argue that claims 1 and 58 have been amended “to specify a human galactosylceramidase coding sequence that "comprises nucleotides 1 to 2055 of SEQ ID NO: 9 or a sequence 95 to
99.9% identical to nucleotides 1 to 2055 of SEQ ID NO: 9 that encodes amino acids 1 to 685 of
SEQ ID NO: 10." Further, claim 4 as amended is an independent claims and specifies a human
galactosylceramidase coding sequence that comprises "a sequence at least 99% identical to
nucleotides 1 to 2055 of SEQ ID NO: 9 that encodes amino acids 1 to 685 of SEQ ID NO: 10."”.
In response to the argument it has been fully considered but is not persuasive due to the claims not being amended to recite the threshold of 99% described in the written description requirement as they still recite a lower limit of 95%. The Applicant has clearly stated in previous remarks that codon optimization would not be obvious since due to degeneracy of the genetic code that would lead to a large number of sequence options to encode for the same wild-type amino acid sequence. Applicant has stated, “Indeed, SEQ ID NO: 9 is less than 76% identical to the native human GALC coding sequence (provided in SEQ ID NO:5). Due to the degeneracy of the genetic code, an extraordinarily large number of sequences ( over 10206 sequences1) are predicted to encode a GALC protein having 685 amino acid residues. The selection of the coding sequence of SEQ ID NO: 9, or a sequence at least 99% identical to SEQ ID NO: 9, is not obvious.” Therefore, to rely on this argument, the SEQ ID NO: 9 comprised in the claimed recombinant AAV vector should be at least 99% identical because the GALC amino acid sequence as seen in SEQ ID NO: 10 is well-known, yet the specific optimized coding sequence is not.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 4, 6, 7, 11-15 remain provisionally rejected and claims 67-69 are newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-18 dated October 22, 2025 of copending Application No. 17/998,330 (hereinafter ‘330). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the cited claims of Application 17/998,330.
Claim 8 of copending application ‘330 is directed to:
A method of treating Krabbe disease in a patient in need thereof, the method comprising intracisternal magna (ICM) administration of the pharmaceutical composition to the patient, wherein the pharmaceutical composition comprises a stock of recombinant AAV (rAAV) having an AAV capsid and a vector genome packaged therein, wherein the vector genome comprises:(a) a 5' inverted terminal repeat (ITR);(b) a CB7 promoter;(c) an intron;(d) a galactosylceramidase (GALC) coding sequence comprising nucleotides 1 to 2055 of SEQ ID NO: 9, or a sequence at least 95% identical thereto that encodes amino acids 1 to 685 of SEQ ID NO: 10;(e) a polvA; and (f) a 3' ITR, and wherein the composition is formulated for administration of a dose of about 1.7 x 1010 genome copies (GC)/g brain mass to about 5.0 x 1011 GC/g brain mass.
Claim 1 of the instant invention is directed to a composition comprising a recombinant adeno-associated virus (AAV), the recombinant AAV comprising: (a) an AAV capsid; and (b) a vector genome comprising (i) a galactosylceramidase coding sequence operably linked to regulatory sequences, wherein the galactosylceramidase coding sequence comprises nucleotides 1 to 2055 of SEQ ID NO: 9 or a sequence 95 to 99.9% identical to nucleotides 1 to 2055 of SEO ID NO: 9 that encodes amino acids 1 to 685 of SEO ID NO: 10; and (ii) AAV inverted terminal repeats necessary for packaging the vector genome in the AAV capsid, wherein the vector genome is packaged in the AAV capsid.
Claim 4 of the instant invention is directed to a composition comprising a recombinant adeno-associated virus (AAV), the recombinant AAV comprising: (a) an AA V capsid; and (b) a vector genome comprising (i) a galactosylceramidase coding sequence operably linked to regulatory sequences, wherein the galactosylceramidase coding sequence comprises a sequence at least 99% identical to nucleotides 1 to 2055 of SEQ ID NO: 9 that encodes amino acids 1 to 685 of SEO ID NO: 10 and (ii) AA V inverted terminal repeats necessary for packaging the vector genome in the AAV capsid, wherein the vector genome is packaged in the AAV capsid.
Thus the claims of the instant application are encompassed by, or overlap in scope significantly with, the claims of copending Application No. 17/998,330. This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
The ‘330 application claims methods, but double-patenting rejections of claims to a method of use based on a claimed composition are proper. This rejection is necessitated by the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc. v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 4, 6, 7, 11-15, and 67-69 are rejected under 35 U.S.C. 103 as being unpatentable over Escolar et al. (US-2019/0336540-A1; of record) in view of Tretiakova et al. (WO-2015/012924-A2; of record IDS filed on January 31, 2022).
Regarding claim 1, Escolar teaches the treatment of Krabbe disease by gene therapy, wherein the treated subject can have any form of Krabbe disease, such as early infantile Krabbe disease, late infantile Krabbe disease, or juvenile Krabbe disease (par 0005, 0074). The vector employed has an AAV2 gene transfer vector backbone (inverted terminal repeats of AAV2 flanking the expression cassette) and an expression cassette with a human cytomegalovirus enhancer; promoter, splice donor, and left-hand intron sequence from chicken B-actin; right-hand intron sequence and splice acceptor from rabbit B- globin (i.e., a chimeric intron) (this enhancer/promoter/intron sequence is referred to as "CAG"). The CAG promoter is a strong ubiquitous promoter used to drive gene expression in AAV vectors. The AAV.rh10-hGALC vector further includes a full-length human galactosylceramidase (GALC) cDNA; and a rabbit B-globin polyA sequence (par 0107; figure 1). The capsid protein is from AAV rh10. The GALC sequences employed are the nucleic acid sequence of SEQ ID No: 1 and the protein sequence of SEQ ID No: 2 (p.4 lines 25-26).
The human GALC protein sequence of Escolar SEQ ID No: 2 is different from SEQ ID No: 10 of the instant application by 1 a.a. (position 641 of SEQ ID No: 10, alignment provided below in Figure 1). However, Escolar teaches other sequences, including Genbank Accession Number. AAH36518.1 (par 0031) which comprises a signal peptide (par 0103), which remains different by 1 a.a. to a.a. 43-685 of instant SEQ ID No: 10, but in a different region than shown in the prior alignment (alignment provided below in Figure 3). A BLAST sequence search of a.a. 43-685 of instant SEQ ID No: 10 reveals it as an isoform of a chimpanzee protein that has a length of 685 amino acids as opposed to the human version that is 669 amino acids in length, regardless both sequences have 100% alignment (alignment provided below in Figure 2). Lastly, Escolar states the GALC coding sequence includes variants that have at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, or at least 99% sequence identity to these GenBank sequences listed, including AAH36518.1 (0031).
The sequence alignments provided below have been included in the Office Action dated September 30, 2024 under the name “NCBI_Blast_SEQIDNO_10__43-685.”
Figure 1: Alignment of Instant SEQ ID NO 10, a.a. 43-685 to Escolar SEQ ID NO: 2, revealing 99% identity with 1 a.a. mismatch:
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Figure 2: Blast of Instant SEQ ID NO 10, a.a. 43-685, revealing 100% identity to Chimpanzee galactocerebrosidase (XP_016782020.1)
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Figure 3: Alignment of Escolar disclosed sequence, AAH36518.1, to Instant SEQ ID NO 10, a.a. 43-685, revealing 99% identity with 1 a.a. mismatch:
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In reference to SEQ ID NO: 9 (2055 nt) the closest sequence similarity was around 90%, which is outside the claimed similarity window (alignment provided in the Office Action under the name “STIC_Search_SEQIDNOS9”; screenshot provided below in Fig. 4). The first two matches with the highest alignments scores were the inventors’ reference(s), followed by the third alignment being of GALC RNA that has 89.8% similarity, and the fourth alignment having a 87.7% similarity. The fourth alignment is from Prevail Ther. (WO 2019/070894) in which the compared sequence, SEQ ID NO: 34, is described as “Gcase protein flanked by two adeno-associated virus (AAV) inverted terminal repeats (ITRs), where one of the ITRs comprises a modified 'D' region relative to a wild-type AAV2 ITR sequence.” The STIC Sequence Searches have been provided in the Office Action dated September 30, 2024 under the name “STIC_Search_SEQIDNOS9”
Figure 4: STIC Sequence Search of SEQ ID NO 9 (codon optimized GALC coding sequence) revealing numerous hits:
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It is understood that SEQ ID NO: 9 encodes a codon optimized GALC coding sequence (p 32, line 20) wherein the encoded amino acid sequence is the same as that encoded in SEQ ID NO: 10. Furthermore, Escolar teaches the GALC sequence may be native or variant GALC sequence, and describes using a non-native nucleotide sequence that translates into the native sequence wherein the codon sequence is degenerate; and further states this is done in order to optimize expression for a specific host cell (0095-0097). “Codon preferences and codon usage tables for a particular species can be used to engineer isolated nucleic acid molecules encoding a GALC protein that take advantage of the codon usage preferences of that particular species. For example, the GALC protein expressed from a vector can be designed to have codons that are preferentially used by a particular organism of interest (e.g., in a mammal with Krabbe disease).” (0098).
Tretiakova teaches “an expression cassette comprising an open reading frame (ORF) for a protein under the control of regulatory sequences which direct expression of the product in cell, which ORF has been modified to preferentially increase expression levels in a selected tissue, wherein the modified ORF is characterized by a triplet frequency of any one of Tables 3 - 12, 16 or 17.” (abstract). The reference teaches a codon optimization method based on the knowledge of codon usage bias which refers to frequency differences in the occurrence of synonymous codons in coding DNA within an organism. The reference acknowledges this is well-known in the art and provides a conventional codon frequency for humans in Table 2 (p 9, par 1). The reference then continues on describing the method of determining codon based on the tissue target within the subject, i.e. CNS and PNS, involving synonymous codon modifications (p 10, par 2; p 11, par 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the GALC sequence taught by Escolar to include the sequence of a similar human relative, the chimpanzee (Pan troglodyte), in particular the breadth of the invention would be extended to be used in clinical trials/toxicology trials upon primates as seen described in the instant specification (Example 5). Secondly, in view of not teaching SEQ ID NO: 9 which is a codon optimized version of the GALC coding sequence based on the Specification description, it would have been obvious to have modified the GALC coding sequence taught by Escolar in view of the codon optimization method and outcomes taught by Tretiakova that would be reasonably expected to improve protein expression within the target tissues for treating Krabbe’s disease. Moreover, Escolar teaches the GALC sequence can be codon optimized to improve protein expression within select tissue. Therefore, it would have been obvious to try in optimizing the standard GALC sequence based on the motivation taught by Escolar with the method of Tretiakova to improve Escolar’s AAV vector.
Regarding claim 4, dependent on claim 1, the limitations listed have been rejected above in claim 1.
Regarding claims 6 and 68, dependent on claim 1 and claim 4 respectively, Escolar teaches wherein the regulatory sequences comprise: a beta-actin promoter sequence, an intron sequence, and a rabbit beta-globin poly A sequence (0103, 0107, 0011; Fig. 1).
Regarding claim 7, dependent on claim 6, Escolar teaches the claimed beta-actin promoter sequence, an intron sequence from chicken β-actin, and a rabbit beta-globin poly A sequence, but does not provide the sequence listings of the regulatory regions used. The instant specification does not describe these sequences being variants or mutated versions of the sequence, and therefore it is understood they are the wild-type sequences. This is supported by the STIC sequence search of the claimed SEQ ID NOs: 13, 15-16 revealing they encode the well-known versions of these regulatory regions as seen below (full alignments provided in Office Action dated September 30, 2024 under the name “STIC_Search_SEQIDNOS13_15_16”; screenshots provided below in Figs. 5-7). Consequently, it is understood that Escolar teaches these sequences based on this rationale.
Figure 5: STIC Sequence Search of SEQ ID NO 13 (beta-actin promoter) revealing numerous 100% identical alignments:
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Figure 6: STIC Sequence Search of SEQ ID NO 15 (intron sequence from chicken β-actin) revealing numerous 100% identical alignments:
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Figure 7: STIC Sequence Search of SEQ ID NO 16 (rabbit beta-globin poly A) revealing numerous 100% identical alignments:
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Regarding claims 11 and 69, dependent on claim 1 and claim 4 respectively, Escolar teaches wherein the vector genome further comprises a 5' ITR of AAV2, the coding sequence and the regulatory sequences, and a 3' ITR of AAV2 (Fig. 1)
Regarding claim 12, dependent on claim 1, Escolar teaches carriers used will depend on the route of delivery of the therapeutic agent wherein acceptable fluids are provided: “water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.” (0041). Moreover, Escolar teaches intrathecal delivery of the AAV vector encoding GALC (0021).
Claim 2 and claim 67 are rejected by dependency to rejected claims 1 and 58, respectively. Allowable subject matter has been acknowledged below.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Escolar et al. (US-2019/0336540-A1; of record) in view of Tretiakova et al. (WO-2015/012924-A2; of record IDS filed on January 31, 2022) as applied to claim 1, and further in view of Dodge et al. (US-2015/0151007-A1; of record).
Regarding claim 13, dependent on claim 1, Escolar teaches various fluids/carriers that can be used in the delivery of the AAV vector to the CNS, and furthermore describes using sorbitol to prevent aggregation of the vector, this can be understood as a surfactant (0109). Escolar does not explicitly teach wherein the composition comprises artificial cerebrospinal fluid (aCSF).
Dodge teaches standard pharmaceutical carriers comprise artificial cerebrospinal fluid (aCSF) and various surfactants (e.g., polysorbates such as “TWEEN 20” and “TWEEN 80”), may be used in combination for delivery of a AAV vector to the CNS (abstract, 0033-34).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used aCSF and a surfactant, based on the work conducted by Dodge wherein AAV vectors were administered to the brain, and both aCSF and a surfactant were included in the composition; therefore, there is a reasonable expectation that the inclusion of these elements in the composition taught by Escolar in view of Tretiakova would function in delivery of the claimed AAV to the CNS as Dodge has shown with AAV.
Claim 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Escolar et al. (US-2019/0336540-A1; of record) in view of Tretiakova et al. (WO-2015/012924-A2; of record IDS filed on January 31, 2022) as applied to claim 1, and further in view of Wilson et al. (WO 2017/075119 A1). The International Patent states the Inventor is “James M. Wison”, but it appears this is a mistake, and is referring to James M. Wilson (An Inventor on the Instant Application).
Regarding claims 14 and 15, both dependent on claim 1, Escolar teaches intrathecal delivery, but only teaches the claimed dosage in relation to intravenous delivery (0007, 0071; 0021). Escolar does not teach wherein the composition is formulated for intrathecal delivery and comprises 1.4 x 1013 to 4 x 1014 GC of the recombinant AAV [claim 14]; and wherein the composition is formulated for intra-cisterna magna delivery and comprises 1.4 x 1013 to 4 x 1014 GC of the recombinant AAV [claim 15].
Wilson teaches the intrathecal delivery and intracisternal delivery via injection into cisterna magna of an AAV vector targeting the CNS (p 7, ln 13- p 8, ln 9) wherein the vector dosage is about 1×109 genome copies (GC) to about 5×1014 GC (p 26, ln 7-24).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used intrathecal delivery or intracisternal delivery at the claimed dosage range, based on the work by Wilson teaching these delivery routes with the claimed dosage based on being within the range taught by Wilson. Altogether, there would be a reasonable expectation that delivery of the claimed AAV via the intrathecal delivery or intracisternal delivery at a dosage of 1.4 x 1013 to 4 x 1014 GC would function in targeting the CNS based on this outcome being described in Wilson.
Allowable Subject Matter:
Regarding claims 2, dependent on claim 1, claim 58, of which claims 60, 62-66 are dependent, and claim 67, the claims recite the AAV capsid as being an AAVhu68 capsid which is listed as SEQ ID NO: 1. The closest prior art reference of Escolar et al. (US-2019/0336540-A1) teaches an AAVrh.10 capsid as listed in Escolar SEQ ID NO: 3, 4 (GenBank Accession Nos. AY243015.1 and AA088201.1) (0017).
A sequence search of instant SEQ ID NO: 1 revealed the earliest mention of the AAVhu68 capsid was by the instant application’s author James Wilson on December 16, 2021 (Hum Gene Ther. 2021 Dec;32(23-24):1439-1449.), which is after the effective filing date. The reference describes the AAVhu68 belonging to clade F that was naturally isolated from human tissue samples (p 1444, col 1, par 1). Moreover, Wilson and Hordeaux (both authors of the instant application) then teach in another publication dated May 16, 2022 (Human gene therapy 33.9-10 (2022): 499-517; of record IDS filed on August 17, 2024) the integration of the AAVhu68 capsid in a AAVhu68 vector expressing a codon-optimized GALC administered into the cisterna magna for the treatment of infantile Krabbe disease (p 500, col 2, par 5; p 501, col 2, par 3-5). Altogether, the limitation of using the AAVhu68 capsid as listed in SEQ ID NO: 1 is allowable subject matter.
Conclusion
Claims 1, 2, 4, 6, 7, 11-15, and 58, 60, 62-69 are rejected. No claims are allowed.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634