DETAILED ACTION
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 .
Application Status
This action is written in response to applicant’s correspondence received on Mar 31, 2025. Claims 1-2, 8, 11-17, 25-28, 32, 46, 48-50, 62 are currently pending and under examination.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application
No. 63/275,390 filed on Nov 03, 2021.
Information Disclosure Statement
The listing of references in the specification (e.g., ([0156], [0130], [0124]. [0105]) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
The Sequence Listing, in ASCII text file is designated 4341_0240002_Seqlisting_ST26.xml and is 16280 B, while the Sequence Listing disclosed in the specification’s incorporation by reference statement is 4341_024PC02_Seqlisting_ST26.xml and is 16280 B. The names of the ASCII text file do not match.
Required response - Applicant must:
• Provide a substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities: SEQ ID NO: 9 is 3321 nucleotides long, but the numbering of its nucleotide sequence goes over 4,000 (pg. 61). There appears to be an issue regarding either the sequence or number in SEQ ID NO: 9, particularly the number jumps from 3050 to 4000 when the each line of sequence increase by 50 nucleotides.
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Appropriate correction is required.
The disclosure is objected to because of the following informalities: [0407] discloses FIG. 6G shows that patient 3 exhibited above normal levels of α-Gal activity that was sustained up to the last measured point at week 28. Then [0407] further discloses patient 2 also showed ~40% reduction in lyso-Gb3 from baseline to week 28, and patient 3 showed ~40% reduction in plasma lyso-Gb3 from baseline within 10 weeks after dosing. However, FIG. 6G does not include data for patient 2. Instead, FIG. 6D-6F demonstrate that “low baseline levels of plasma lyso-Gb3 remained steady over time ([0406]). An appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink ([0150]) and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term BIACORE®, KINEXA®, Replagal®, Myleran®, Busulfec® ([0158], [0159], [0144], [0250]) which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. It is recommended that Applicant review the specification for additional uses of terms that are trade name or mark used in commerce.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 1-2, and 13-14 are objected to because of the following informalities:
In claim 1, line 7, the acronym “α-Gal A” is defined as being “α galactosidase A”. However, the acronym has previously been defined in claim 1. Similarly, claim 2 recites acronyms “AAV”, “α-Gal A”, and “vg/kg” that have previously been defined in claim 1. An acronym should only be defined the first time it appears in an independent claim or in the group of claims under an independent claim.
Claims 13 and 14 recite “the promotor” which contains a typographical error for “promoter”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 8, 11-17, 25-28, 32, 46, 48-50, 62 are 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. Those claims included in the statement of rejection but not otherwise discussed are rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claims 1 and 2 recites the limitation “an α galactosidase A transgene encoding the at least one α-Gal A protein”. There is insufficient antecedent basis for this limitation in the claim. There is no prior recitation of “at least one α-Gal A protein” in the claim. It is unclear which “at least one α-Gal A protein” the claim is referring to. It is unclear whether the claim intends to recite an AAV expression vector comprising an α-Gal A expression cassette which comprises an α-Gal A transgene encoding at least one α-Gal A protein or encoding specific α-Gal A proteins.
Claim 26 recites “a biological sample having greater than about 9.6% inhibition of α-Galactosidase A activity”, which renders the claim indefinite. The recitation of “greater than” is a limitation that requires a baseline, e.g., 9.6%, while the recitation of “about” denotes an approximate range. Thus, it is unclear what value the recitation of “greater than” is intended to exceed. Further, it is unclear whether the claim requires inhibition of α-Galactosidase A activity to be greater than 9.6% (>9.6%), which does not include 9.6%. It is unclear whether the claim requires inhibition of α-Galactosidase A activity to be about 9.6%, which includes values less than, equal to, and greater than 9.6%. Without clarity, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 27 recites “decreases the amount of glycosphingolipids in the subject by at least about 2 fold”, which renders the claim indefinite. The recitation of “at least” is a limitation that requires a baseline value, e.g., 2, while the recitation of “about” denotes an approximate range. Thus, it is unclear what value the recitation of “at least” is intended to exceed. Further, it is unclear whether the claim requires the amount of glycosphingolipids to be decreased by at least 2 fold (≥2) which includes values equal to and greater than 2. It is unclear whether the claim requires the amount of glycosphingolipids to be decreased by about 2% which includes values less than, equal to, and greater than 2. Without clarity, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 32 recite “in one or more of plasma, liver, heart, kidney, urine, skin, or spleen”, which renders the claim indefinite. It is unclear what is meant by “one or more” in the claim. For instance, plasma and urine are bodily fluids, whereas liver, heart, kidney, skin, and spleen are organs. It is unclear how “one or more” would apply to a singular organ such as the heart or skin. It is unclear how “one or more” would apply to bodily fluids such as plasma and urine. Accordingly, the scope of this limitation cannot be reasonably ascertained.
Claim 49 recites “wherein the subject is not administered a preconditioning treatment”, which renders the claim indefinite. The specification teaches the term “preconditioning” refers to “using a chemotherapy conditioning agent, such as for example, busulfan” ([0250], line 4). In addition, “the conditioning agent can be used e.g., for ex vivo lentiviral gene therapy to deplete/kill the bone marrow cells” ([0250], lines 5-6). The term “preconditioning” is defined by using exemplary language. It is unclear whether the claimed “preconditioning treatment” is limited to chemotherapy conditioning agents that encompasses busulfan, or further includes other types of treatments.
Claim 62 recites wherein the subject has been administered with an enzyme replacement therapy (ERT) for Fabry disease prior to the administering”. It is unclear what “the administering” refers to. It is unclear whether the ERT for Fabry disease is administered prior to the administration of the ERT itself or prior to administering the AAV expression cassette recited in claim 1, from which claim 62 depends. It is unclear whether the administration of the ERT is administered prior to additional treatment, e.g., pre-treatment recited in the claim.
Claim 62 also recites (“pre-treatment”) in line 3, which renders the claim indefinite. MPEP 2173.05(d) states "Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. It is unclear whether the claim is limited to administering an enzyme replacement therapy for Fabry disease, which is one type of “pre-treatment” recognized by the specification ([0289]). It is unclear whether the claim is limited to administering a pre-treatment for Fabry disease, which encompasses enzyme replacement therapy and non-enzyme replacement therapy.
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, 8, 11, 13, 14, 16-17, 25-28, 32, 46, 48-50, and 62 are 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the 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”. MPEP § 2163 further states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species.
Claim 1 recites “a sequence encoding a signal peptide” with no sequence, length, or a specific function. Thus, the breadth of claim 1 is drawn to possession of a genus of signal peptides (SP) defined by (i) broadly providing any signal and (i) structure of a peptide.
The specification discloses the AAV expression vector can comprise any signal peptide ([0265]), and further teaches one species, a SP of human α-galactosidase A comprising the amino acid sequence of SEQ ID NO: 10 ([0275]). The claim covers any SP including but not limited to albumin, IgG, and synthetic peptides. However, the specification fails to identify common structural characteristics that would allow one skilled in the art to recognize members of the genus. The specification also fails to disclose a recognized correlation between structure and function to demonstrate possession of the entire genus. MPEP 2163 explains that “[f]or inventions in an unpredictable art, an adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus”, and “when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus”.
The art does not establish common structural characteristics shared among members of the genus. Owji (European Journal of Cell Biology; 2018, 97:422-441) teaches SP is “a general term referred to a wide variety of signaling sequences" (pg. 424, left-column, para. 1), particularly about 50% of B. subtitilis extracellular proteins contain SPs, more than 90% of E. coli's secretory proteins are SP-dependent, and over 20% of mouse and human proteome possesses SPs (pg. 424, left-column, para. 3). Owji teaches SPs play different roles in diverse secretory pathways (Table 2), and range from 25 to 140 residues with remarkable differences in their aa compositions responsible for their protein translocation capabilities (pg. 427, right-column, para. 2). Further, Owji teaches that signal peptides exhibit a variety of structures including but not limited to mitochondrial targeting peptide composed of domains for matrix signal, chloroplast targeting peptide composed of additional three domains, and bacterial signal peptides composed of different combinations of N-region, H-region, and C-region (FIG. 3).
Further, dependent claims are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein, except claims 12 and 15 that narrow the scope to a specific species within the genus, an α-GalA signal peptide.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of signal peptides, one skilled in the art would conclude that Applicant was not in possession of the claimed genus of sequences encoding any signal peptide.
Claim 8 is 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.
Claim 8 recites “a mutated Woodchuck Hepatitis Virus (WHV) Posttranscriptional Regulatory Element (WPRE) sequence” (emphasis added). The specification discloses the WPRE sequence “can be any wild-type or mutated WPRE sequence” ([0265]). Thus, the breadth of claim 8 is drawn to possession of a genus of mutated WPRE sequences not defined by structure as members of the genus can be of any length with any mutation, including insertion, deletion, and/or substitution.
The specification mentions that in some embodiments the mutated WPRE sequence comprises mut6, which is a 592bp DNA containing promoter region of WHV X protein followed by a truncated form of X protein (0270]). However, the specification fails to disclose (i) which type of mutations and how many of them are permitted, and (ii) which region of the WPRE sequence could tolerate mutations. The claimed genus of mutated WPRE sequences read on any mutations, including ones that would abolish function. See guidance of MPEP 2163 discussed above.
Regarding the stat of the art, the specification further cites US 10,179,918 for teachings of wild-type and mutated WPRE sequences ([0265]). Cost (US 10,179,918; Pub Date: Jan 15, 2019) demonstrates activity of three WPRE sequences when paired with zinc-finger nucleases (FIG. 1), and teaches the effect of the WPRE is highly variable between different cells and/or expression vectors: sometimes tis inclusion has no effect on transgene or mRNA levels; sometimes its inclusion improves transgene expression; and in some instances, sometimes its inclusion actually inhibits transgene expression (col. 13, para. 4). Thus, the state of the art teaches highly unpredictable effects of any mutations within a WPRE sequence.
In contrast, dependent claims 13 and 14 narrow the scope to a specific mut6 WPRE sequence comprising the nucleotide sequence of SEQ ID NO: 6 remedy the lack of written description therein.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of mutated WPRE sequence, one skilled in the art would conclude that Applicant was not in possession of the claimed genus encoding any mutated WHV WPRE sequence.
Claim 11 is 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.
Claim 11 recites a “codon-optimized α-GalA sequence” (emphasis added). The specification discloses codons are optimized “to increase biological activity and/or alteration of transcriptional and translational regulatory sequences to improve gene expression” ([0267]). Accordingly, the breadth of the claim is drawn to possession of a genus of α-GalA sequence defined by function and the structure of an α-GalA protein.
The specification discloses one species: codon-optimized hGLA transgene with the same amino acid sequence as the native hGLA protein ([0269]). See guidance of MPEP 2163 discussed above. The specification does not disclose the optimization method and codons changed from the native to codon-optimized protein, including key codons responsible for improved gene expression. The specification does not compare biological activity or gene expression before and after codon optimization.
The state of the art does not establish that codon optimization of mRNA sequences encoding the same protein can predictably improve gene expression. Mauro (Trends Mol. Med.; 2014, 20(11):604-613) teaches the following (pg. 611, left-column):
Codon optimization is often suggested as a primary consideration for generating high-expressing constructs suitable for gene therapy and genetic vaccines. Although protein expression can be increased using these approaches, it is evident, however, that mRNAs contain numerous layers of information that overlap the amino acid code and that this complexity can be disrupted by
codon optimization. A more serious problem is that the scientific basis of codon optimization, at least in mammals, does not support that codon usage is rate-limiting for protein expression. In addition, there are potentially serious consequences associated with using codon optimization,
particularly for nucleic acid therapeutics. In the absence of analysis; these potential problems include: (i) disrupting the normal patterns of cognate and wobble tRNA usage, affecting protein structure and function; (ii) producing novel peptides with unknown biological activities; and (iii) altering post-transcriptional modifications that may modify protein ensembles. (emphasis added)
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of codon optimizations in mRNAs to increase biological activity and/or to improve gene expression, one skilled in the art would conclude that Applicant was not in possession of the claimed genus any codon-optimized α-GalA sequence.
Claims 1-2, 8, 11-17, 25-28, 32, 46, 48-50, 62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating Fabry disease in a human subject comprising administering an AAV expression cassette comprising an α-Gal A transgene of SEQ ID NO: 5, does not reasonably provide enablement for a method of ameliorating one or more symptoms associated with Fabry disease in a human subject in need thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of the Claims
The claims are directed to a method of ameliorating one or more symptoms associated with Fabry disease in a human subject in need thereof. The specification refers the term “ameliorating” to “any therapeutically beneficial result in the treatment of a disease state”, including lessening in the severity or progression ([0200]). The specification discloses that in some aspects, the subject has one of the listed symptoms ([0223]). The specification also discloses the term “Fabry disease” refers to classical Fabry disease, late-onset Fabry disease, and hemizygous females having mutations in the gene encoding an α-Gal A ([0163]); accordingly, the human subject population required in the claims broadly encompasses subjects within these genera. Thus, the breadth of the claims is drawn to a method of ameliorating any symptoms associated with Fabry disease in various human subject populations spanning different disease stages.
Guidance of the Specification
The specification discloses the method ameliorates one or more of the following symptoms: globotriaosylceramide (Gb3) levels above normal, globotriaosylsphingosine (lyso-Gb3) levels above normal, renal disease, cardiac disease, anhidrosis, acroparesthesia, angiokeratoma, gastrointestinal (GI) tract pain, corneal and lenticular opacities, or cerebrovascular disease ([0223]). Example 2 teaches only one symptom, lyso-Gb3 levels are assessed from a total of 9 patients (FIG. 3, [0397]). The specification provides no guidance on which symptoms are expected to respond upon administration of claimed AAV expression cassette comprising an α-Gal A transgene. The specification also fails to provide guidance on the correlation between plasma α-Gal A activity and clinical symptoms for all human subjects encompassed within the breadth of the claims, including males and females.
Working Examples
The specification discloses assessment of lyso-Gb3 from a total of 9 patients (FIG. 3, [0397]). Patients 1 and 2 exhibited normal levels of α-Gal A activity that was sustained for 18 months and 1 year, respectively (FIG. 6C, 6E), but low baseline levels of plasma lyso-Gb3 remained steady over time ([0405]-[0406]). Accordingly, the administration and expression of α-Gal A transgene did not ameliorate one of the symptoms associated with Fabry disease in a human subject in need thereof. Similary, the baseline levels of plasma lyso-Gb3 remained steady over time for patients 4-8 (FIG. 6L, 6N, 6O, 6P), while data is not available for patient 9 (FIG. 6Q). Patient 3 is the only one exhibiting ~40% reduction in plasma lyso-Gb3 from baseline within 10 weeks after dosing and maintained through week 52 (FIG. 6I, [0407]). The clinical observations are patients 1-3 reported improvement in ability to sweat ([0405]-[0406]). However, these observations are not quantified without statistical analysis. No symptoms data are reported for different subject populations encompassed within the breadth of the claims.
State of the Art
Bichet (Genetics in Medicine; Jan 2021, 23(1):192-201) discloses “changes in plasma lyso-Gb3 levels did not correlate with changes in measures of clinical disease progression (VMi, eGFR, or pain) in treatment-naïve or ERT-experienced patients (pg. 198, right-column, para. 2; Table 2-4). Bichet teaches “neither the lyso-Gb3 concentration at baseline, lyso-Gb3 concentration during treatment, absolute decrease of lyso-Gb3, nor the relative decrease of lyso-Gb3 predicted the risk of clinical events in patients [of Fabry disease] receiving [enzyme replacement therapy]” (pg. 193, left-column, para. 3). Bichet recognizes that “substrate accumulation alone does not explain disease severity and therapeutic response to a given treatment” (pg. 193, left-column, end of para. 3). Therefore, measurements of lyso-Gb3 levels post administration of AAV expression vector comprising an α-Gal A transgene as the only quantified results, do not teach any one of the symptoms associated with Fabry disease listed in instantly specification ([0223]) would be ameliorated.
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to test each symptom listed in [0223] in each patient subject population listed in [0163] in controlled clinical studies. These studies span from measuring progression of Gb3 levels, renal disease, cardiac disease, anhidrosis, acroparesthesia, angiokeratoma, gastrointestinal (GI) tract pain, corneal and lenticular opacities, or cerebrovascular disease, each comprising complicated and non-overlapping symptoms. Further, each study would need proper controls, e.g., not receiving claimed α-Gal A transgene and not receiving enzyme replacement therapy prior to administration of the claimed α-Gal A transgene. Follow-up studies are also required to demonstrate any changes of slowly progressing symptoms associated with Fabry disease. The specification provides a protocol with 52 after dosing and up to 72 weeks of follow-up per subject ([0393]), but plasma lyso-Gb3 levels are recorded for only 8 patients after different time periods. Thus, one ordinary skill in the art would need to have to establish which measurements or diagnostic marker could reliably track amelioration as the prior art reports that lyso-Gb3 levels do not present significant correlation with therapeutic response to a given treatment of Fabry disease.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an unreasonable amount experimentation would be required to make and use the invention as claimed. Therefore, the claims are not considered to be fully enabled by the instant disclosure.
Claim Interpretation
In claim 2 the recitation of “wherein the α-Gal A transgene comprises the nucleotide sequence as set forth in SEQ ID NO: 5”, in claims 13 and 14 the recitation of “the nucleotide sequence as set forth in SEQ ID NO: 2”, “the nucleotide sequence as set forth in SEQ ID NO: 3”, “the nucleotide sequence as set forth in SEQ ID NO: 4”, “the nucleotide sequence as set forth in SEQ ID NO: 5”, “the nucleotide sequence as set forth in SEQ ID NO: 6”, “the nucleotide sequence as set forth in SEQ ID NO: 7”, and in claim 15 the recitation of "the nucleotide sequence as set forth in SEQ ID NO: 9” are interpreted to encompass only nucleotide sequences that comprise the full length of SEQ ID NO, with or without additional nucleotides at either or both ends.
Claim 62 recites “wherein the subject has been administered with an enzyme replacement therapy (ERT) for Fabry disease prior to the administering (“pre-treatment”)”, which renders the claim indefinite (see discussion above under 112(b)). The specification discloses “the pre-treatment ERT comprises an enzyme replacement therapy” ([0290], and an AAV expression cassette is administered to Fabry disease patients who are on ERT ([0359], [0377]). Accordingly, claim 62 is interpreted wherein the subject has been administered with one type of pre-treatment, in particular ERT for Fabry disease, prior to the administration of the AAV expression cassette of claim 1.
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 following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 8, 11-17, 27-28, 32, 46, 48, 50, and 62 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huston (US 2020/0239911 A1; Pub Date: Jul 30, 2021; IDS received on 12/19/2024, Cite No. US69).
Regarding claim 1, Huston teaches a method of treating Fabry disease in a human subject comprising administering an adeno-associated virus (AAV) serotype 2/6 expression construct comprising (i) alipoprotein E (APOE) enhancer operably linked to an alpha 1-antitrypsin (hAAT) promoter, (ii) a human hemoglobin beta (HBB)-IGG intron, (iii) a sequence encoding a signal peptide, (iv) a α galactosidase A (α-Gal A) transgene encoding α-Gal A protein comprising the nucleotide sequence of SEQ ID NO: 9 (e.g., GALco), and (v) a bovine growth hormone (bGH) poly A signal sequence (claims 31, 35, and 38; FIG. 1B illustrated below). Huston further teaches wherein the AAV expression vector is administered at a dose of 5x1012 vector genomes per kilogram of body weight (vg/kg) to 1x1014 vg/kg (claim 40). In particular, Huston discloses clinical dose cohorts of 5x1012 vg/kg, 1x1013 vg/kg, and 5x1013 vg/kg in accordance with recommendation of the Safety Monitoring Committee ([0322]). Accordingly, the claimed range of vg/kg is taught by Huston.
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Regarding claim 2, the teachings of Huston are discussed above as applied to claim 1. Further, Huston teaches wherein the α-Gal A transgene comprises the nucleotide sequence from 1052 to 2341 in SEQ ID NO: 9 (Table 1, pg. 12), which is 100% identical to instant SEQ ID NO: 5 (both ends of the sequence alignment are reproduced below).
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Regarding claim 8, Huston further teaches wherein the α-Gal A expression cassette further comprises a mutate Woodchuck Hepatitis Virus WPRE sequence (claim 31; Table 1, pg. 13).
Regarding claim 11, Huston further teaches wherein the α-Gal A transgene comprises a wild-type α-Gal A sequence or a codon-optimized α-Gal A sequence (claim 34).
Regarding claim 12, Huston further teaches wherein the signal peptide is an α-Gal A signal peptide (FIG. 1B, [0057]).
Regarding claims 13 and 14, the teachings of Huston on the α-Gal A transgene comprising the nucleotide sequence as set forth in instant SEQ ID NO: 5 are discussed above as applied to claim 2. Huston further teaches the following components with locations in respect to SEQ ID NO: 9 and nucleotide sequences that match 100% to instant claimed SEQ ID NOs: (i) the enhancer of SEQ ID NO: 2 located at nucleotides 141-461 (instant SEQ ID NO: 2), (ii) the promoter of SEQ ID NO: 3 located at nucleotide 471-863 (instant SEQ ID NO: 3), (iii) the intron of SEQ ID NO: 4 located at nucleotide 867-999 (instant SEQ ID NO: 4), (iv) the α-Gal A transgene located at nucleotide 1052-2341 of SEQ ID NO: 9 (instant SEQ ID NO: 5), (v) the mutated WPRE of SEQ ID NO: 6 located at nucleotide 2364-2955 (instant SEQ ID NO: 6), (vi) the poly A signal sequence of SEQ ID NO: 7 located at nucleotide 2962-3186 (instant SEQ ID NO: 7). The sequence alignments are highlighted below.
Qy = instant SEQ ID NO: 2
Db = SEQ ID NO: 2 of Huston
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Qy = instant SEQ ID NO: 3
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Qy = instant SEQ ID NO: 4
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Qy = instant SEQ ID NO: 6
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Qy = instant SEQ ID NO: 7
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Regarding claim 15, Huston further teaches wherein the α-Gal expression cassette comprises the nucleotide sequence as set forth in SEQ ID NO: 9 that is 100% identical to instant SEQ ID NO: 9 (pg. 13-14).
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Regarding claim 16, Huston further teaches wherein the AAV expression vector serotype is AAV2/6 (claim 39).
Regarding claim 17, Huston further teaches wherein the subject has one or more of the recited symptoms including but not limited to globotriaosylceramide levels above normal, globotriaosylsphingosine levels above normal, and renal disease (claim 32).
Regarding claim 27, Huston further teaches wherein the α-Gal A protein expressed from the transgene decreases the amount of glycosphingolipids in the subject by at least about 2-fold compared to untreated subjects (i.e., subject prior to the administration) (claim 18).
Regarding claim 28, Huston further teaches wherein the α-Gal A protein expressed from the transgene decreases the amount of glycosphingolipids in the subject by at least about 80% (claim 48).
Regarding claim 32, Huston further teaches wherein the α-Gal A protein expressed from the transgene decreases the amount of glycosphingolipids in one or more of the subject’s plasma, liver, heart, kidney, or spleen (claim 49).
Regarding claim 46, Huston further teaches wherein the subject is administered an immunosuppressant prior to and/or during administration of the AAV expression vector (claim 44).
Regarding claim 48, Huston further teaches “variant #4” expression construct was evaluated in two groups of subjects, where one received rituximab and methylprednisolone (i.e., immunosuppressants) while another group “received variant #4 expression construct at the highest dose…but no immunosuppression administration” ([0295]). The structure of variant #4 is illustrated below (FIG. 1A), which comprises all required components recited in instant claim 1. Thus, Huston teaches instant claim limitation wherein the subject is not administered an immunosuppressant prior to and/or during administration of the AAV expression vector.
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Regarding claim 50, Huston further teaches wherein the expression of at least one α-Gal A protein is sustained for at least 3 months, at least 9 months, or at least 12 months (claim 46).
Regarding claim 62, Huston further teaches the method of treatment is given to subjects who received enzyme replacement therapy (ERT) prior to study enrollment, and particularly these subjects should continue to receive ERT during the study, unless ERT is withdrawn ([0324]). Huston further teaches subjects previously treated with ERT undergo administration of the AAV expression vector ([0332], [0341]). Thus, Huston teaches wherein the subject has been administered with an ERT for Fabry disease prior to the administration of the AAV expression vector.
Claim Rejections - 35 USC § 103
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 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 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Huston (cited supra) as applied to claim 1 above, and further in view of Lenders (JASN; 2016, 27:256-264) and Linthorst (Kidney International; 2004, 66:1589-1595).
Regarding claims 25-26, Huston is applied to the relevant teachings of claim 1 as discussed above and are incorporated herein by reference. Huston further teaches treatment for Fabry disease also involves enzyme replacement therapy (ERT), which patients may develop neutralizing antibodies to α-Gal A ([0092]). “In fact, 50% of males treated with agalsidase alfa and 88% of males treated with agalsidase beta developed α-Gal A antibodies. Importantly, a significant proportion of those antibodies are neutralizing antibodies.”([0093]). Further, Huston teaches subjects who received ERT ([0324]) undergo administration of the AAV expression vector comprising the α-Gal A transgene ([0332], [0341]). Thus, Huston teaches the subject has pre-existing anti-α-Gal A antibodies prior to administering the AAV expression vector. Huston also teaches that α-Gal A activity in plasma should be monitored for subjects on ERT and throughout the study ([0341]).
However, Huston does not teach wherein the pre-existing anti-α-Gal A antibodies are determined by an enzyme-linked immunosorbent assay (ELISA) or that the subject has greater than about 9.6% inhibition of α-Galactosidase A activity.
Lenders teach patients who receive recombinant enzyme replacement therapy (ERT) based on infusion of recombinant agalsidase enzymes, as treatment for Fabry disease may develop endogenous inhibition of agalsidase by antibodies (pg. 256, para. 1). Using an in vitro GLA inhibition assay reported by Linthorst, Lenders observed 44 male patients who received ERT have a mean 50% ERT inhibition of agalsidase-α (FIG. 1A) and 19 of them exhibit up to 76.8+/- 14.3% inhibition (FIG. 1C). "As a consequence, especially male patients are under high risk for therapy escape or therapy resistance. Hence, the clinical parameters of these patients should be carefully followed-up, including measurements of serum-mediated ERT inhibition" (pg. 261, left-column).
As demonstrated by Linthorst, the in vitro GLA inhibition assay is ELISA coated with agalsidase enzymes, followed by incubation of serial dilutions of serum containing anti-α-GalA neutralizing antibody (1591, left-column, "ELISA for the detection of anti-rh-α-Gal A IgG antibodies"). In addition, Linthorst confirms that "all IgG-positive sera by ELISA showed a marked in vitro inhibition of enzyme activity ranging from 65% to 95%" (1592, left-column, para. 2). Linthorst also discloses "emergence of antibodies with in vivo neutralizing capacities is frequently encountered in treated Fabry disease patients" (pg. 1589, left-column, conclusion), and "the occurrence of antibodies results in hypersensitive reactions in some patients, necessitating lengthening of infusion time and/or the use of premedications" (pg. 1590, left-column, para. 2).
It would have also been obvious to one of ordinary skill in the art before the effective filling date of the invention to have determined whether a subject has pre-existing anti-α-Gal A antibodies by ELISA as taught by Lenders and Linthorst because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. Lenders and Linthorst teach that ELISA is a known fluorescent enzyme assay to detect anti-α-GalA antibodies in the serum of patients undergoing enzyme replacement therapy. Thus, one would have been motivated have done so in order to monitor the clinical parameters of these patients, particularly serum-mediated ERT inhibition as acknowledged by Huston, Lenders, and Linthorst. One would have had a reasonable expectation of success in doing so because Lenders and Linthorst both demonstrate ELISA predictably reports the presence of anti-α-Gal A antibodies in Fabry patients’ serum.
It would have also been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the patient population of Huston to male patients exhibiting greater than 9.6% inhibition of α-Gal A activity as taught by Lenders that this is a known subpopulation of Fabry disease patients. This modification would have merely amounted to a simple substitution of one known patient population (male and female patients in the method of Huston) to another (male patients with anti-α-GalA neutralizing antibody from ERT). One would have been motivated to have done so because Lenders teach that these male patients are under high risk for therapy escape or therapy resistance (pg. 261, left-column) and Linthorst supports that the occurrence of antibodies results in hypersensitive reactions, requiring lengthening of infusion time and/or the use of premedications (pg. 1590, left-column, para. 2). Further, Huston’s method provides continuous endogenous expression of α-Galactosidase A in the liver, which is an alternative therapy for patients positive of anti-α-GalA neutralizing antibodies developed from periodic infusions of ERT. One would have had a reasonable expectation of success in doing so because Huston teaches the method is applicable for subject who have received ERT prior to administration of the AAV expression vector comprising the α-Gal A transgene ([0332], [0341]). Thus, Huston already teaches treating patients positive for anti-α-GalA neutralizing antibodies with claimed method is predictable.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Huston (cited supra) as applied to claim 1 above, and further in view of Freeline Therapeutics (“Freeline Doses Second Patient of Phase ½ MARVEL-1 Clinical Trial for Fabry Disease; Globe Newswire; Released June 16, 2021; Accessed on Oct 01, 2026; hereinafter as Freeline).
Regarding claim 49, Huston is applied to the relevant teachings of claim 1 as discussed above and are incorporated herein by reference. Huston further teaches introducing the α-Gal A expression cassette into hematopoietic stem cell for subsequent implantation into a patient ([0095]).
However, Huston does not teach wherein the subject is not administered a preconditioning treatment prior to the administration of the AAV expression vector.
Freeline teaches an AAV gene therapy for Fabry disease, referred to as FLT190, that consists of an AAVS3 engineered capsid with an expression cassette comprising a codon-optimized human GLA cDNA under the control of a liver-specific promoter FRE1 (pg. 2, para. 2). Freeline further teaches the treatment is administered by intravenous infusion lasting approximately one hour and “does not require the patient to undergo stem cell harvest or conditioning with chemotherapy” (pg. 2, para. 2). Instant specification discloses the term “preconditioning” refers to using a chemotherapy conditioning agent ([0250]). Accordingly, Freeline teaches a method of treating Fabry disease in a subject without administering a preconditioning treatment prior to administration of an AAV expression vector.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filling date of the invention to have modified the method of Huston to not precondition the subject prior to the treatment as taught by Freeline because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. Huston teaches a method of treating Fabry disease comprising expressing GLA transgene in the liver through stem cell harvesting and subsequent implantation into patient ([0082], [0095]). Freeline also teaches a similar treatment comprising expressing GLA transgene in the liver without requiring stem cell harvest or conditioning with chemotherapy (pg. 2, para. 2). Thus, one would have been motivated to substitute the step prior to administration of the GLA expression cassette from ex vivo to in vivo without preconditioning as taught by Freeline for the advantage of avoiding stem cell collection, implantation, and chemotherapy. One would have had a reasonable expectation of success in doing so because both Huston and Freeline teach liver expression of a GLA transgene, and Freeline demonstrates in two patients that this approach does not require preconditioning (pg. 1, para. 1).
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, 8, 11-17, 25-28, 32, 46, 48-50, 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 5, 16, and 18 of U.S. Patent No. US 11,219,695 in view of Huston (US 2020/0239911 A1; Pub Date: Jul 30, 2021; IDS received on 12/19/2024, Cite No. US69), Lenders (JASN; 2016, 27:256-264), Linthorst (Kidney International; 2004, 66:1589-1595), and Freeline Therapeutics (“Freeline Doses Second Patient of Phase ½ MARVEL-1 Clinical Trial for Fabry Disease; Globe Newswire; Released June 16, 2021; Accessed on Oct 01, 2026).
Regarding instant claim 1, claim 16 of ‘695 recites a method of treating Fabry disease in a subject in need thereof, comprising administering an adeno-associated virus (AAV) expression construct comprising (i) an apolipoprotein E (APOE) enhancer linked to an alpha 1-antitrypsin (hAAT) promoter, (ii) a human hemoglobin beta (HBB)-IGG intron, (iii) an α-GalA transgene encoding at least one α-Gal A protein, (iv) a bovine growth hormone poly A signal sequence, and (v) an α-Gal A signal peptide.
However, ‘695 does not recite wherein the AAV expression vector is administered at the instantly claimed dose.
Huston is applied to the relevant teachings of claim 1 as discussed previously and are incorporated herein by reference. Huston teaches an AAV expression vector comprising the instantly recited components for treatment of Fabry disease, and wherein the AAV expression vector is administered at the instantly claimed range ([0322]).
Thus, it would have been obvious to one of ordinary skill in the art to have administered ‘695’s AAV expression vector to treat Fabry disease at the claimed dosage as taught by Huston because it would have merely amounted to a simple combination of prior art elements according to known method to yield predictable results. Each element in the combination performs the same function as it does separately. One would have been motivated to have followed Huston’s guidance to administer ‘695’s AAV expression vector as Huston teaches this dosage is in accordance with recommendation of the Safety Monitoring Committee ([0322]). One would have had a reasonable expectation of success in doing so because ‘695 and Huston’s AAV expression vector comprises identical components (i) to (v).
Regarding instant claim 2, the obviousness to administer ‘695’s AAV expression vector at the instantly claimed dosage as taught by Huston is discussed above as applied to instant claim 1. Further, Huston teaches wherein the α-Gal A transgene comprises the nucleotide sequence as set forth in instant SEQ ID NO: 5 (see sequence alignment above).
Thus, it would have been obvious to one of ordinary skill in the art to have modified ‘695’s α-Gal A transgene to instant SEQ ID NO: 5 as taught by Huston because it would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. This modification is simply substituting a generic α-Gal A transgene of ‘695 to a specific α-Gal A transgene of Huston. One would have been motivated to have done so and one would have had a reasonable expectation of success in doing so because Huston teaches AAV expression vector comprising this particular α-Gal A transgene can be used to treat Fabry disease.
Regarding instant claims 11, 12, and 27, ‘695 recite instant limitations in claims 4, 5, and 18, respectively.
Regarding instant claims 2, 8, 13-17, 25-26, 28, 32, 46, 48-50, and 62, all instant limitations are addressed because they are either recited in patented claims or are render obvious by prior art in view of Huston, Lenders, Linthorst, and Freeline, whose teachings are discussed supra and are incorporated herein by reference. All obviousness arguments above are also incorporated herein.
Claims 1-2, 8, 11-17, 25-28, 32, 46, 48-50, 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 9, and 17 of U.S. Patent No. US 12,630,839 in view of Huston, Lenders, Linthorst, and Freeline Therapeutics (all cited supra).
Regarding instant claims 1, 2, 8, 13, and 14, claim 1 of ‘839 recites an adeno-associated virus (AAV) expression construct comprising: (i) an apolipoprotein E (APOE) enhancer comprising the nucleotide sequence as set forth in SEQ ID NO: 2 that is 100% identical to instant SEQ ID NO: 2, and it is linked to an alpha 1-antitrypsin (hAAT) promoter comprising the nucleotide sequence set forth in SEQ ID NO: 3 that is 100% identical to instant SEQ ID NO: 3; (ii) a human hemoglobin beta (HBB)-IGG intron comprising the nucleotide sequence as set forth in SEQ ID NO: 4 that is 100% identical to instant SEQ ID NO: 4; (iii) an α-GalA transgene encoding at least one α-Gal A protein comprising the nucleotide sequence as set forth in SEQ ID NO: 5 that is 100% identical to instant SEQ ID NO: 5; (iv) a bovine growth hormone poly A signal sequence comprising the nucleotide sequence as set forth in SEQ ID NO: 6 that is 100% identical to instant SEQ ID NO: 6; and (v) an α-Gal A signal peptide comprising the nucleotide sequence as set forth in SEQ ID NO: 7 that is 100% identical to instant SEQ ID NO: 7. The obviousness to administer ‘839’s AAV expression vector at the instantly claimed dosage as treatment for Fabry disease as taught by Huston is discussed above as applied to patented claims of U.S. Patent No 11,219,695.
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Regarding instant claims 12, 15, and 16, ‘839 recite instant limitations in claims 9, 17, and 7, respectively. ‘839 recites the AAV expression vector comprises the nucleotide sequence as set forth in SEQ ID NO: 9 that is 100% identical to instant SEQ ID NO: 9.
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Regarding instant claims 11, 17, 25-28, 32, 46, 48-50, and 62, all instant limitations are addressed because they are either recited in patented claims or are render obvious by prior art in view of Huston, Lenders, Linthorst, and Freeline, whose teachings are discussed supra and are incorporated herein by reference. All obviousness arguments above are also incorporated herein.
Claims 1-2, 8, 11-17, 25-28, 32, 46, 48-50, 62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 34, 36-38, and 40 of copending Application No. 17/572,189 (allowed claims filed on 02/25/2026) in view of Huston, Lenders, Linthorst, and Freeline Therapeutics (all cited supra).
Regarding instant claim 1, claims 34 and 36 of ‘189 recites an adeno-associated virus (AAV) expression construct comprising (i) an apolipoprotein E (APOE) enhancer linked to an alpha 1-antitrypsin (hAAT) promoter, (ii) a human hemoglobin beta (HBB)-IGG intron, (iii) an α-GalA transgene encoding at least one α-Gal A protein, (iv) a bovine growth hormone poly A signal sequence, and (v) an α-Gal A signal peptide. The obviousness to administer ‘189’s AAV expression vector at the instantly claimed dosage as taught by Huston is discussed above as applied to patented claims of U.S. Patent No 11,219,695.
Regarding instant claims 11, 12, and 27, ‘189 recite instant limitations in claims 37, 34, and 40, respectively.
Regarding instant claims 2, 8, 13-17, 25-26, 28, 32, 46, 48-50, and 62, all instant limitations are addressed because they are either recited in copending claims or are render obvious by prior art in view of Huston, Lenders, Linthorst, and Freeline, whose teachings are discussed supra and are incorporated herein by reference. All obviousness arguments above are also incorporated herein.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 8, 11-17, 25-28, 32, 46, 48-50, 62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 10-11, 17-20, 32, 34-35, 39-40, 44, 46-49, 58, 61-63, and 69-70 of copending Application No. 19/652,515 (claims filed on 04/20/2026) in view of Huston, Lenders, Linthorst, and Freeline Therapeutics (all cited supra).
Regarding instant claims 1, 2, 8, 13, and 14, claims 69 and 70 of ‘515 recites an adeno-associated virus (AAV) expression construct comprising: (i) an apolipoprotein E (APOE) enhancer comprising the nucleotide sequence as set forth in SEQ ID NO: 2 that is 100% identical to instant SEQ ID NO: 2, and it is linked to an alpha 1-antitrypsin (hAAT) promoter comprising the nucleotide sequence set forth in SEQ ID NO: 3 that is 100% identical to instant SEQ ID NO: 3; (ii) a human hemoglobin beta (HBB)-IGG intron comprising the nucleotide sequence as set forth in SEQ ID NO: 4 that is 100% identical to instant SEQ ID NO: 4; (iii) an α-GalA transgene encoding at least one α-Gal A protein comprising the nucleotide sequence as set forth in SEQ ID NO: 5 that is 100% identical to instant SEQ ID NO: 5; (iv) a bovine growth hormone poly A signal sequence comprising the nucleotide sequence as set forth in SEQ ID NO: 6 that is 100% identical to instant SEQ ID NO: 6; and (v) an α-Gal A signal peptide comprising the nucleotide sequence as set forth in SEQ ID NO: 7 that is 100% identical to instant SEQ ID NO: 7. ‘515 also recites a method of treating Fabry disease by administering an expression construct comprising instantly claimed components (claim 35). ‘515 recites the expression vector is administered at a broader dosage (claims 11, 40, and 62). The obviousness to administer ‘515’s AAV expression vector at the instantly claimed dosage as treatment for Fabry disease as taught by Huston is discussed above as applied to patented claims of U.S. Patent No 11,219,695.
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Regarding instant claim 11, ‘515 recite instant limitations (claims 2, 34, and 58).
Regarding instant claim 15, ‘515 recites wherein the expression vector comprises the sequence of SEQ ID NO: 9 that is 100% identical to instant SEQ ID NO: 9 (claims 4 and 63).
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Regarding instant claim 16, ‘515 recites instant limitations (claims 16, 39, and 61).
Regarding instant claim 17, ‘515 recites instant limitations (claim 32).
Regarding instant claim 27, ‘515 recites instant limitations (claims 18 and 47).
Regarding instant claim 28, ‘515 recites instant limitations (claims 19 and 48).
Regarding instant claim 32, ‘515 recites instant limitations (claims 20 and 49).
Regarding instant claim 46, ‘515 recites instant limitations (claim 44).
Regarding instant claim 50, ‘515 recites instant limitation (claims 17 and 46).
Regarding instant claims 25-26, 48-49, and 62, all instant limitations are addressed because they are either recited in copending claims or are render obvious by prior art in view of Huston, Lenders, Linthorst, and Freeline, whose teachings are discussed supra and are incorporated herein by reference. All obviousness arguments above are also incorporated herein.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 8, 11-17, 25-28, 32, 46, 48-50, 62 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2, 6-8, and 18 of copending Application No. 19/749,039 (claims filed on 07/21/2026) in view of Huston, Lenders, Linthorst, and Freeline Therapeutics (all cited supra).
‘039 recites viral vector comprising (i) an α-GalA transgene encoding at least one α-Gal A protein, and (ii) an α-Gal A signal peptide for expression in a cell of a subject with Fabry disease (claims 2, 8, and 18). Claims 6 and 7 of ‘039 recite limitations in instant claims 11 and 27. The obviousness to administer ‘039’s viral vector in a method to treat Fabry disease and at the instantly claimed dosage as taught by Huston is discussed above as applied to patented claims of U.S. Patent No 11,219,695. Further, all instant limitations are addressed because they are either recited in copending claims or are render obvious by prior art in view of Huston, Lenders, Linthorst, and Freeline, whose teachings are discussed supra and are incorporated herein by reference. All obviousness arguments above are also incorporated herein.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights