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 application is in response to the papers filed on March 4, 2026. Pursuant to the amendment filed on March 4, 2026, claims 8-15, 18, and 26-31 are currently pending of which claims 8, 12-14, and 18 (which is not properly identified as amended) have been amended, and claims 9, and 16-17 have been cancelled. It is noted in the Remarks filed on March 4, 2026 claim 18 is improperly listed as cancelled rather than claim 16. No new claims have been added.
Therefore, claims 8-15, 18, and 26-31 are currently under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No PCT/US2021/031802, filed May 11, 2021. Applicant’s claim for the benefit of prior-filed parent provisional applications: 63/073,756 filed on September 2, 2020, 63/070,653 filed on August 26, 2020, and 63/023,459 filed on May 12, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is May 12, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 4, 2026 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants' arguments or amendments:
Specification
In view of Applicants’ amendment to the Specification filed on March 4, 2026, in which the Abstract has been amended, the objection to the Specification has been withdrawn.
Claim Objections
In view of Applicants’ amendments to the claims dated March 4, 2026, wherein claim 9 has been cancelled, the objection to claim 9 for being a substantial duplicate has been rendered moot.
Claim Rejections - 35 USC § 112(b)
In view of Applicants’ amendments to the claims dated March 4, 2026, wherein claims 8, 12-14, and 18 have been amended and claims 9, and 16-17 have been cancelled, the rejection to claims 8-18 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, have been withdrawn.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendments to the claims dated March 4, 2026, wherein claims 8, 12-14, and 18 have been amended, and claims 9, and 16-17 have been cancelled, the rejection to claims 8, 10-15, and 18 rejected under 35 U.S.C. 103 as being unpatentable over Escolar et al. (US-2019/0336540-A1) in view of Taghian et al. (Molecular Therapy 28.2 (2020): 411-421), Abeliovich et al. (US-2020/0071680-A1) and Wilson et al. (WO-2015/012924-A2), have been withdrawn. The rejections to now cancelled claims 9, 16 and 17 have been rendered moot.
The rejections have been withdrawn in view of the amendments to the pending claims, and furthermore to provide a clearer record in relation to the SEQ ID Nos recited in the claims. The references employed remain in the new grounds of rejection presented below, but now include Salamat-Miller et al. that teaches a GALC protein sequence in relation to SEQ ID NO:10, that was obtained from a new STIC sequence search.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
Claims 8, 10-15, 18, and 26-31 are newly rejected under 35 U.S.C. 103 as being unpatentable over Escolar et al. (US-2019/0336540-A1) in view of Taghian et al. (Molecular Therapy 28.2 (2020): 411-421), Abeliovich et al. (US-2020/0071680-A1), Salamat-Miller et al. (US-2011/0318324-A1) and Wilson et al. (WO-2015/012924-A2). This is a new rejection necessitated by Applicants' amendments to the claims in the response filed on March 4, 2026.
Escolar teaches treatment of Krabbe disease by gene therapy, wherein the treated subject can have any form of Krabbe disease, and wherein the route of delivery is intrathecal administration (par 0005, 0021, 0074). Escolar teaches the vector as being a recombinant AAV (rAAV) , specifically AAV.rh10 that “includes of an AAV2 gene transfer vector backbone (inverted terminal repeats of AAV2 flanking the expression cassette); an expression cassette with a human cytomegalovirus enhancer; promoter, splice donor, and left-hand intron sequence from chicken β-actin; right-hand intron sequence and splice acceptor from rabbit β-globin (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 GALC cDNA; and a rabbit β-globin polyA sequence (FIG. 1).” (Fig. 1., par 0107). The capsid protein is from AAV rh10 (par 0107). The GALC sequences employed are the nucleic acid sequence of SEQ ID No: 1 and the protein sequence of SEQ ID No: 2 (par 0071). Furthermore, Escolar teaches the viral vector is administered at a dose of at least 1×1011 gc/kg to at least 4×1014 gc/kg (par 0071). It is noted the Specification describes the claimed CB7 promoter as “composed of hybrid between a CMV IE enhancer and a chicken β-actin (CB) promoter” (p 4-5); and Escolar is expected to teach this promoter by describing the promoter as “The CAG promoter is composed of human cytomegalovirus (CMV) enhancer, chicken β-actin promoter” (par 0011; Fig. 1).
Escolar does not teach the full SEQ ID NO: 9, the method comprising intracisternal magna (ICM) administration of the pharmaceutical composition, and the specific dosage described based on teaching different units than what is claimed (GC/kg of subject vs GC/g brain mass).
The human GALC protein sequence of Escolar (SEQ ID No: 2) is different from instant application SEQ ID No: 10 by only 1 a.a., in particular position 641 of SEQ ID No: 10 (Threonine vs. Alanine) as seen in the alignment provided below in Figure 1. Escolar lists several GALC sequences, such as the NCBI Reference Sequence: NP_000144.2, and 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 the listed GenBank sequences (par 0031). This alignment was provided in the previous Office Action, wherein there is a single amino acid difference at amino acid 641.
Figure 1: Alignment of Instant SEQ ID NO 10 to Escolar SEQ ID NO: 2, revealing 99% identity with 1 a.a. mismatch at location 641:
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Salamat-Miller teaches SEQ ID NO: 2 that is 100% similar to instant SEQ ID NO: 10, and states the encoded sequence as the full-length precursor human galactocerebrosidase enzyme (par 0012, 0121). The STIC sequence search that comprises this sequence alignment is provided with this Office Action.
In reference to the nucleotide sequence the vector comprises, i.e. SEQ ID NO: 9 (2055 nt), the closest sequence similarity was around 90%, which is outside the claimed similarity window (provided in the previous Office Action under the name “STIC_Search_SEQIDNO9”; screenshot provided below in Fig. 2). The first two matches with the highest alignments scores were the inventors’ reference(s), followed by results 3-5 being of GALC RNA that have 89.8% similarity, and results 6-9 having a 87.7% similarity. These last results are from Prevail Therapeutics. (e.g. US Application No. 16/690,320, published as US Pub. US 2020/0071680 A1; herein referred to as Abeliovich et al.) in which the compared sequence of Result 6, SEQ ID NO: 34, is described as “the isolated nucleic acid comprises a GALC-encoding sequence” and in some embodiments is codon optimized (e.g., codon optimized for expression in mammalian cells, for example human cells) (par 0010; 0084).
Figure 2: STIC Sequence Search of SEQ ID NO 9 (codon optimized GALC coding sequence):
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It is understood that instant 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).
In further support of codon optimized sequences, Wilson 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). Wilson describes determining the codon optimization based on the tissue target within the subject, i.e. brain, involving synonymous codon modifications (p 10, par 2; p 11, par 2).
In reference to the dosage and route of delivery, Taghian teaches a safe and reliable technique for CNS delivery of AAV vectors in the cisterna magna that achieves broad distribution of AAV gene transfer to the CNS (abstract). Additionally, the method involves the AAV dose that is administered to the patient being based on the brain weight of the subject, and describes “The dose was determined, scaled up from preclinical experiments performed in mice, non-human primates, cats, and sheep.” (p 417, col 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 encode the human GALC full-length precursor sequence wherein a threonine has been substituted by an alanine as this sequence was known and readily available before the effective filing date of the instant application as taught by Salamat-Miller.
Secondly, in reference to the codon optimized version of the nucleotide sequence of the instant vector, SEQ ID NO: 9, it would have been obvious to modify the known coding sequence because Escolar teaches wherein codon optimization can be used in view of the “particular organism of interest” for the GALC coding sequence (par 0098). In support of this, Abeliovich et al. teaches a sequence that is 87.7 % similar to instant SEQ ID NO: 9, and states codon optimized can be used for expression in mammalian cells, or more specifically for human cells. Additionally, Wilson teaches particular codon optimization methods, and for select expression in human cells, and more specifically tissue types, e.g. CNS. Altogether, it would have been obvious to optimize expression of the vector by codon optimizing the GALC sequence, and moreover the codon optimized version is considered an obvious variant of the wild-type sequence for improving outcomes related to using the vector for treating Krabbe disease.
Lastly, in reference to the differences in the units used for the dosage of the composition to be administered, Escolar not teach the dosage based on brain weight, but rather subject weight. However, in cases where the claimed ranges overlap or lie inside ranges disclosed by the prior art, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257,191 USPQ 90 (CCPA 1976); ln re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990), MPEP 2144.05). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close (see Titanium Metals Corp. of America v. Banner, 778 F.2d 775,783,227 USPQ 773, 779 (Fed. Cir. 1985), MPEP 2144.05). It would have been obvious to modify the dosages of the vector that is to be administered to the cerebral spinal fluid via administering through the cisterna magna, based on brain weight since it is the tissue type being targeted for treatment of Krabbe disease, and because similarly Taghian teaches such approach with other AAV vectors wherein dosage is based on brain weight when this route of delivery is employed. Moreover, it would be obvious to deduct such values, based on the known dosages used by Escolar, and further basing these values on the subject’s brain weight.
Regarding claim 10, dependent on claim 8, Escolar teaches the method further comprising hematopoietic stem cell transplant or bone marrow transplant before or after administration of the pharmaceutical composition (“Such methods can include ablating bone marrow in the subject (for example using chemotherapy, radiation, or both), and subsequently administering a therapeutically effective amount of hematopoietic stem cells (HSCs) to the subject to provide the subject with a new immune system.” (par 009)).
Regarding claim 11, dependent on claim 10, Escolar teaches the method wherein the hematopoietic stem cell (HSC) transplant or bone marrow transplant permits a reduced dose of the rAAV to be administered to the patient based on there being a reduced chance of an immune response that would occur after ablation of the bone marrow followed by HSC transplant and gene vector delivery. With a reduced immune response, e.g. antibody production, there is an expectation that a higher dosage of the gene vector is not required since the vectors will not be attacked, and gene therapy success would subsequently increase based on increased vector survival and targeted GALC expression in CNS tissues (par 0009, 0112).
Regarding claim 12-14, the rejection above to claim 8 describes the obviousness rationale to optimize the dosage based on Escolar’s teaching of a similar vector with dosages, and in view of Taghian teaching the route of delivery and optimizing the dosage based on a subject’s brain weight. The claims are all similar except for different preambles.
In reference to the claim 12 preamble, “A method for increasing GALC expression and enzyme activity in the serum and/or cerebral spinal fluid (CSF) of a patient having Krabbe disease,” Escolar teaches increased GALC expression or activity in a subject being treated for Krabbe disease in their CNS and/or PNS, wherein the CSF is analyzed (par 0062, 0067, 0090, 0258).
In reference to the claim 13 preamble, “A method for reducing neuroinflammation in peripheral nerves of a patient having Krabbe disease”, Escolar teaches the reduction of neuroinflammation as seen in control of nerve inflammation after administration of the vector (par 0155-0156).
In reference to the claim 14 preamble, “A method for increasing GALC expression and activity in neurons of the cortex and/or hippocampus of a patient having Krabbe disease,” Escolar “ increases in GALC activity may be observed in the CNS and / or PNS, such as in the brain , spinal cord, cerebellum , and/or peripheral nerves ( such as the sciatic)”, and therefore there is a reasonable expectation that cortex and/or hippocampus which are comprised in the brain would be also have increased expression of GALC. Furthermore, it is noted that Escolar teaches testing for increased GALC expression in the cortex (par 0159, 0166, Table 2). Altogether, the preambles for claims 12-14 are taught by Escolar.
Furthermore, a preamble is generally not accorded patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). It is expected that the same method steps recited in these claims, for which are taught by Escolar in view of Taghian et al., Abeliovich et al., Salamat-Miller et al. and Wilson et al as seen in the rejections above, would lead to these outcomes described in these preambles as there are no additional limitations of method steps that would lead to these predictable outcomes.
Regarding claims 15, 26, 28, and 30 dependent on claims 10, 12, 13, and 14, respectively, Escolar teaches wherein the patient is less than two months, less than six months, or less than twelve months of age (“In some examples, the subject is a human infant less than 6 months of age.” (par 0052, 0117)).
Regarding claims 18, 27, 29, and 31, dependent on claims 10, 12, 13, and 14, respectively, Escolar teaches the blood and/or CSF psychosine levels are reduced after treatments and any biomarker of disease progression in a treated Krabbe patient, and therefore it would be obvious to measure if similar outcomes are observed in the claimed invention (par 0028, 0060).
Response to Applicants' Arguments as they apply to rejection of claims under 35 USC § 103
Starting on page 6 of the remarks filed on March 4, 2026, Applicants essentially argue the following:
“With respect to Escolar, Applicant notes that claimed rAAV of the invention does not contain the protein of SEQ ID NO: 10. The rAAV carries a vector genome having a novel coding sequence of SEQ ID NO: 9, or a sequence at least 99% identical thereto which encodes the same protein. The Office Action describes search results for SEQ ID NO: 9. There is no teaching or suggestion in Escolar or Abeliovich of SEQ ID NO: 9. As noted in the Office Action, the closest sequence identify had 89.8% identity. This is well outside the scope of the claims. Further, as noted by the examiner, the protein of Escolar differs from SEQ ID NO: 10.”
“Further, there is no teaching or suggestion of this nucleic acid sequence in combination with the other vector genome elements in an rAAV capsid as defined by the claimed invention, or a method of using this rAAV at the dose recited in the claims.”
In response to the argument it has been fully considered but is not persuasive due to the following reasons:
Regarding the first presented argument, the new rejection above describes that the claimed SEQ ID NO: 9, a codon-optimized nucleic acid sequence of GALC, remains obvious in view of the wild-type sequence being known in the art, and furthermore codon optimization techniques also being known in the art as a way to increase select protein expression in select cell types, i.e. mammalian cells. Such codon optimization techniques are described by both Abeliovich and expanded upon by Wilson, by stating
“Codon usage bias has been reported for numerous organisms, from viruses to eukaryotes. Since the genetic code is degenerate (i.e., each amino acid can be coded by on average three different codons), the DNA sequence can be modified by synonymous nucleotide substitutions without altering the amino acid sequence of the encoded protein. Such synonymous codon optimization has been performed for the purpose of optimizing expression in a desired host, as described in the scientific literature and in patent documents.” (p 1, par 3); “Using the information provided herein…, one may design modified genes having codons which preferentially enhance expression levels in a selected target tissue… The target tissue may be a secreting or non-secreting organ, tissue or cell type, e.g., skeletal muscle, brain, ocular photoreceptor cells” (p 10, par 2).
Therefore, there is a reasonable expectation of success that one of ordinary skill in the art can codon optimize the known GALC sequence to arrive at the claimed SEQ ID No: 9. In relation to the amino acid sequence, SEQ ID NO: 10, the rejection above describes this sequence being known in the art as taught by Salamat-Miller that teaches 100% sequence similarity, and describes the sequence as the human full-length precursor sequence of GALC. Additionally, teaches a sequence that is 99% similar, and states the amino acid sequence of the vector can be 99% similar to the sequence.
If the claimed codon optimization sequence is not obvious in view of the prior art, then unexpected results should be provided to show the employed sequences are different than the wild-type version and codon-optimized versions that can be predicted with known codon optimization tables in relation to outcomes pertaining to treating Krabbe disease.
Regarding the second presented argument: In response to applicant's arguments against the references individually, 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). The references recited above in the new grounds of rejection teach all the limitations currently recited in the claims.
Conclusion
Claims 8-15, 18, and 26-31 are rejected. No claims are 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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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634