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
This action is in response to the papers filed February 18, 2026.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/18/2026 has been entered.
Claim Amendments
Applicant’s amendment to the claims filed 12/17/2025 is acknowledged.
Claims 1-50, 61-70 have been cancelled.
Claims 51-60 are pending and under examination.
Election/Restrictions
The following is a summary of the restriction/election requirements in the application. See the Requirement for Restriction/Election mailed 11/21/2024.
Applicant elected with traverse of invention of Group 1 (methods), and the therapeutic payload SERPINA1, in the reply filed 01/23/2025.
Rejoinder: The restriction requirement between alternative therapeutic payloads, as set forth in the Requirement for Restriction/Election mailed 11/21/2024, is hereby withdrawn. Accordingly, claim 58, previously withdrawn from consideration pursuant to 37 CFR 1.142(b), has been rejoined and fully examined for patentability under 37 CFR 1.104.
In view of the above rejoinders and/or withdrawal of the restriction requirements, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Priority
The instant application 17/603,935 was filed on 10/14/2021. This application is a national stage of international application PCT/US20/28102 filed 04/14/2020, claiming priority based on U.S. Provisional Application No. 62/833,875 filed 04/15/2019.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 08/19/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Applicant’s remarks filed 12/17/2025 have been carefully considered, but are found moot in view of the new grounds of rejection set forth in this action.
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.
Claims 51-60 are rejected under 35 U.S.C. 103 as being unpatentable over US 2017/0088856 A1 to Barzel et al.; in view of US 6,632,800 B1 to Russell et al.; and WO 2018/058002 A1 to Bleakley et al.
This rejection is newly applied.
Regarding claim 51, Barzel teaches administration of gene therapy construct comprising from 5' to 3', a polynucleotide sequence encoding (a) a 5' homology arm, (b) a 2A coding sequence encoding a 2A peptide, (c) a therapeutic payload, and (d) a 3' homology arm, wherein the gene therapy construct integrates at an endogenous albumin target site is transcribed to produce albumin-2A and the therapeutic payload as separate proteins. See, e.g., Figures 1, 8; paragraphs 7, 14, 122-124.
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Barzel teaches a step of detecting the on-target integration and expression of the therapeutic payload by measuring a 2A peptide in a biological sample from the subject who has received the integrating gene therapy construct. In particular, Western blot analysis was used qualitatively to determine the presence or absence of the 2A peptide probe. See, e.g., Figures 5, 11D; paragraphs 11, 17, 119 and 129.
Barzel does not teach quantifying the level of the therapeutic payload by quantifying the 2A peptide level in the biological sample, whereby the 2A peptide level serves as a surrogate for the level or amount of the therapeutic payload, as instantly claimed in claim 51.
Russell is relevant prior art for teaching a strategy for monitoring the expression of a transgene in a patient. The method of monitoring the production of a therapeutic polypeptide in a patient comprises (a) administering to a patient a nucleic acid construct encoding a therapeutic polypeptide and a marker polypeptide, and (b) detecting the marker polypeptide which has been released into the extracellular body fluid of the patient as an indication of the amount of therapeutic polypeptide produced from the nucleic acid construct. See, e.g., Abstract; col. 1, ll. 33-50. The strategy is applicable to gene therapy. See, e.g., col. 4, ll. 59-61.
The step of detecting is specifically-described as a step of quantifying, and the level of expression of the transgene is monitored by quantifying the marker peptide in a biological fluid sample from the patient. See, e.g., col. 1, ll. 51, to col. 2, ll. 11. Various quantitative techniques are contemplated. See, e.g., col. 10, ll. 9-28. For optimal monitoring of the expression of the transgene, expression of the marker polypeptide should be linked to expression of the therapeutic transgene such that there is a fixed stoichiometric relationship between the expression of the two genes. See, col. 5, ll. 45-49.
Preferably, the nucleic acid construct encodes the transgene product, a linker and the marker polypeptide, all under the control of a single promoter, resulting in the expression of a fusion protein comprising each element and, therefore, assuring that the marker and the transgene product are synthesized in stoichiometric proportion, which enhances the value of the marker as an indicator of the level of transgene expression. See, col. 8, ll. 18-48. In one embodiment, the “linker” is a self-cleaving 2A peptide, resulting in spontaneous release of the marker from the therapeutic protein. See, col. 12, ll. 43-65.
Accordingly, Russell is found to teach or fairly suggest a method of monitoring expression of a therapeutic payload in a subject who has received a gene therapy construct, comprising quantifying the level of the therapeutic payload by quantifying the level of a 2A peptide in a biological sample from the subject, wherein the level of 2A peptide serves as a surrogate for the level of the therapeutic payload. The system provides a convenient and effective means of monitoring the level and kinetics of the expression of transgenes in patients without the need for disruptive and expensive sampling, such as surgery. See, col. 3, ll. 52-57.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the method of Barzel by further including a step of quantifying the level of the therapeutic payload by quantifying the 2A peptide level in the biological sample, whereby the 2A peptide level serves as a surrogate for the level or amount of the therapeutic payload, in view of the teachings of Russell, with a reasonable expectation of success because the expression of the 2A peptide and therapeutic payload are linked in a fixed stoichiometric relationship, and, therefore, quantifying the level of 2A peptide provides a convenient and effective means of monitoring the level of the therapeutic payload in a patient who has received the gene therapy construct without the need for disruptive and expensive sampling.
Barzel and Russell do not disclose the nucleotide sequence encoding P2A according to SEQ ID NO: 2, as claimed in claim 51.
Bleakley is relevant prior art for disclosing a construct (SEQ ID NO: 62) comprising a P2A sequence and SEQ ID NO: 2. See alignment:
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Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the invention of Barzel by using a P2A sequence according to SEQ ID NO: 2, as found in Bleakley, with a reasonable expectation of success because Barzel teaches that the gene therapy construct encodes P2A, and, therefore, one of ordinary skill in the art would have sought a suitable P2A coding sequence known in the art, as found in Bleakley.
For these reasons, claim 51 would have been prima facie obvious over the prior art.
Regarding dependent claim 52, Barzel discloses that the length of the 5' and 3' arms are 1.3 and 1.4-kb, respectively (par. 14). The homology arms may also be 1 kb in length (par. 48).
Regarding dependent claims 53-58, Barzel discloses that the therapeutic payload encodes alpha-1-antitrypsin (SERPINA1), which has cell-intrinsic or cell-extrinsic activity that promotes a biological process to treat patient in need. See paragraphs 100 and 104. Alpha-1-antitrypsin (SERPINA1) is also expressed intracellularly, secreted extracellularly and normally expressed in the liver. The therapeutic payload may alternatively encode Factor IX (see, e.g., par. 100; Figure 1), which is a peptide that is normally expressed in liver cells. Various other therapeutic payloads are contemplated. See, e.g., par. 100. In some embodiments, the therapeutic payload is ectopically expressed in liver disease. See, par. 107.
Regarding dependent claim 59, Barzel discloses that integration of the gene therapy construct does not substantially disrupt expression of the albumin encoded at the target site. See, e.g., Figure 1; paragraphs 50-51.
Regarding dependent claim 60, Barzel discloses that the gene therapy construct is an AAV vector, See, e.g., paragraphs 41-43.
Claims 51-60 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/032986 A1 to Chau et al., published 02/13/2020 and filed 10/30/2018; in view of US 6,632,800 B1 to Russell et al.
This rejection is newly applied.
Regarding claim 51, Chau teaches administration of gene therapy construct comprising from 5' to 3', a polynucleotide sequence encoding (a) a 5' homology arm, (b) a 2A coding sequence encoding a 2A peptide, (c) a therapeutic payload, and (d) a 3' homology arm, wherein the gene therapy construct integrates at an endogenous albumin target site is transcribed to produce albumin-2A and the therapeutic payload as separate proteins. See, e.g., paragraph 6 and Figure 2.
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Chau further discloses that albumin is produced normally in the subject, and the C-terminal 2A peptide tag serves as a circulating biomarker to indicate successful integration and expression of the transgene encoding the therapeutic payload. See paragraphs 81.
Chau does not teach quantifying the level of the therapeutic payload by quantifying the 2A peptide level in the biological sample, whereby the 2A peptide level serves as a surrogate for the level or amount of the therapeutic payload, as instantly claimed in claim 51.
Russell is relevant prior art for teaching a strategy for monitoring the expression of a transgene in a patient. The method of monitoring the production of a therapeutic polypeptide in a patient comprises (a) administering to a patient a nucleic acid construct encoding a therapeutic polypeptide and a marker polypeptide, and (b) detecting the marker polypeptide which has been released into the extracellular body fluid of the patient as an indication of the amount of therapeutic polypeptide produced from the nucleic acid construct. See, e.g., Abstract; col. 1, ll. 33-50. The strategy is applicable to gene therapy. See, e.g., col. 4, ll. 59-61.
The step of detecting is specifically-described as a step of quantifying, and the level of expression of the transgene is monitored by quantifying the marker peptide in a biological fluid sample from the patient. See, e.g., col. 1, ll. 51, to col. 2, ll. 11. Various quantitative techniques are contemplated. See, e.g., col. 10, ll. 9-28. For optimal monitoring of the expression of the transgene, expression of the marker polypeptide should be linked to expression of the therapeutic transgene such that there is a fixed stoichiometric relationship between the expression of the two genes. See, col. 5, ll. 45-49.
Preferably, the nucleic acid construct encodes the transgene product, a linker and the marker polypeptide, all under the control of a single promoter, resulting in the expression of a fusion protein comprising each element and, therefore, assuring that the marker and the transgene product are synthesized in stoichiometric proportion, which enhances the value of the marker as an indicator of the level of transgene expression. See, col. 8, ll. 18-48. In one embodiment, the “linker” is a self-cleaving 2A peptide, resulting in spontaneous release of the marker from the therapeutic protein. See, col. 12, ll. 43-65.
Accordingly, Russell is found to teach or fairly suggest a method of monitoring expression of a therapeutic payload in a subject who has received a gene therapy construct, comprising quantifying the level of the therapeutic payload by quantifying the level of a 2A peptide in a biological sample from the subject, wherein the level of 2A peptide serves as a surrogate for the level of the therapeutic payload. The system provides a convenient and effective means of monitoring the level and kinetics of the expression of transgenes in patients without the need for disruptive and expensive sampling, such as surgery. See, col. 3, ll. 52-57.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the method of Chau by further including a step of quantifying the level of the therapeutic payload by quantifying the 2A peptide level in the biological sample, whereby the 2A peptide level serves as a surrogate for the level or amount of the therapeutic payload, in view of the teachings of Russell, with a reasonable expectation of success because the expression of the 2A peptide and therapeutic payload are linked in a fixed stoichiometric relationship, and, therefore, quantifying the level of 2A peptide provides a convenient and effective means of monitoring the level of the therapeutic payload in a patient who has received the gene therapy construct without the need for disruptive and expensive sampling.
Chau further discloses that the construct comprises the nucleic acid sequence of SEQ ID NO: 15. See paragraph 25 and Figure 7B. Chau’s SEQ ID NO: 15 contains the P2A sequence according to SEQ ID NO: 2 of the instant application. See alignment:
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For these reasons, claim 51 would have been prima facie obvious over the prior art.
Regarding dependent claim 52, Chau teaches that the homology arms have a length of 800-1,200 nucleotides. See, par. 15. In at least one example, both homology arms have a length of 1000 bp (see, e.g., Fig. 7B), which is equivalent to 1 Kb.
Regarding dependent claims 53-58, in at least one example, Chau teaches the therapeutic payload encodes Factor IX (see, e.g., par. 144), which has cell-intrinsic or cell-extrinsic activity that promotes a biological process to treat patient in need. Factor IX is also expressed intracellularly, secreted extracellularly and normally expressed in the liver. In some embodiments, the therapeutic payload is ectopically expressed in liver disease. See, par. 107.
Regarding dependent claims 53-58, in at least one embodiment, Chau discloses that the therapeutic payload encodes alpha-1-antitrypsin (A1AT, encoded by SERPINA1). See, e.g., par. 146. A1AT has cell-intrinsic or cell-extrinsic activity that promotes a biological process to treat patient in need, and is expressed intracellularly, secreted extracellularly and normally expressed in the liver. The therapeutic payload may alternatively encode Factor IX (see, e.g., par. 144), which is a peptide that is normally expressed in liver cells. In some embodiments, the therapeutic payload is ectopically expressed in a liver disease. See, e.g., par. 92, 104.
Regarding dependent claim 59, Chau discloses that the construct does not disrupt endogenous albumin gene expression. See, e.g., par. 16.
Regarding dependent claim 60, Chau teaches that the construct is an AAV vector. See, e.g., Figure 2.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Wohlgensinger et al. (2010) “Signed outside: a surface marker system for transgenic cytoplasmic proteins” Gene therapy, 17(10), 1193-1199, discloses a system in which the expression of a cytoplasmic transgene product is linked to, and can be monitored by, the coexpression of a cellular surface marker. A single open reading frame was created encoding a therapeutic transgene (p47phox) linked to a surface marker protein (∆LNGFR) by a 2A peptide. In this 2A-mediated coexpression system, the detection of the surface marker provides an indirect measure for the expression of the cytoplasmic transgene product by FACS surface staining. The system may be applied for gene therapy (GT) monitoring. See, e.g., Abstract; pg. 1193; pg. 1197-1198, joining paragraph; and Figure 1.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
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/JAMES JOSEPH GRABER/Examiner, Art Unit 1631