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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 20, 2025 has been entered.
Status of Claims / Response to Amendment
This office action is in response to an amendment filed on November 20, 2025.
Claims 1-2, 9, 11-12, 16, 19-20, 22, 25, 38, 48, 50, 53, 56, 63, 66, 67, and 69 were previously pending. Applicant amended claims 2, 9, and 25; cancelled claims 1, 16, 20, 48, 50, 53, 56, 53, 66-67 and 69; claim 71 is newly added.
Claims 2, 9, 11-12, 19, 22, 25, 38 and 71 are currently pending, with claim 19 withdrawn.
Claims 2, 9, 11-12, 22, 25, 38 and 71 are under consideration.
All of the amendment and arguments have been thoroughly reviewed and considered. All of the previously presented rejections have been withdrawn as being obviated by the amendment of the claims.
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
This office action contains new grounds for rejection necessitated by amendment.
Priority
The priority date of the instant claims 2, 9, 11-12, 22, 25, 38 and 71 is 10/15/2018, filling date of the US provisional application NO. 62/745,859.
Claim Interpretation -- Updated
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
For the purpose of applying prior art, claim 2 has been amended to recite "isolating adeno-associated virus (AAV) particles from a feed." The term "feed" is not expressly defined in the application's disclosure. Thus, under BRI and within the context of the claim, the term "feed" is interpreted to encompass any AAV-containing composition.
For the purpose of applying prior art, claim 2 has been amended to recite a "pharmaceutical unit dosage," which is not expressly defined by the application's disclosure. The specification in para. [00122] provides definition for "unit dose":
"A “unit dose” refers to a physically discrete unit suited as a unitary dosage for the subject to be treated; each unit containing a predetermined quantity optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, is calculated to produce a desired effect (e.g., prophylactic or therapeutic effect). "
Thus, under BRI and in light of the specification, the term "pharmaceutical unit dosage" is interpreted as a unit containing any quantity1 of prophylactic or therapeutic agent.
Claim 2 recites the term “parallel-line model,” which is defined the applicant's disclosure in para [0035]:
"The parallel-line method is a robust biostatistical analysis method for comparing one or more test substances against a reference substance based on their relative potency. Finney, D.J., Statistical method in biological assay (Charles Griffin & Co., Ltd. 1952); Wardlaw, A.C., Practical Statistics for Experimental Biologists 210 (Wiley 1986) (2000)."
Claim 11 recites "about," which is defined by the applicant's disclosure in para [0021]:
“[0021] "About" modifying, for example, the quantity of an ingredient in the compositions, concentration of an ingredient in the compositions, flow rate, rAAV particle yield, feed volume, salt concentration, and like values, and ranges thereof, employed in the methods provided herein, refers to variation in the numerical quantity that can occur, for example, through typical measuring and handling procedures used for making concentrates or use solutions; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make the compositions or carry out the methods; and like considerations. The term "about" also encompasses amounts that differ due to aging of a composition with a particular initial concentration or mixture. The term "about" also encompasses amounts that differ due to mixing or processing a composition with a particular initial concentration or mixture. Whether or not modified by the term "about" the claims include equivalents to the quantities. In some embodiments, the term "about" refers to ranges of approximately 10-20% greater than or less than the indicated number or range. In further embodiments, "about" refers to plus or minus 10% of the indicated number or range. For example, "about 10%" indicates a range of 9% to 11 %.”
Thus, under BRI, the term "about" in claim 11 is interpreted to encompass ranges of 20% greater than or less than the indicated number. For instance, "about 24 hours" is construed to mean a range from 19.2 to 28.8 hours.
Claim Rejections - 35 USC § 112(b) -- New
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.
Claims 2, 9, 11-12, 22, 25, 38 and 71 are rejected under 35 U.S.C. 112(b), 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.
Claim 2 has been amended to recite "d) using the AAV genome titer determined in step b) and the relative infectivity determined in step c) to produce a pharmaceutical unit dosage comprising AAV particles," which is indefinite because it is unclear what constitutes "using."
The 86-page specification mentions methods involving the production of a pharmaceutical unit dosage only in paragraphs [0013] and [0098]. Of these, only paragraph [0098] discloses an embodiment of methods that include determining genome titer and infectivity:
"[0098] In some embodiments, the disclosure further provides methods for producing a pharmaceutical unit dosage comprising isolated recombinant adeno associated virus (rAAV) particles, comprising isolating rAAV particles from a feed comprising an impurity (for example, rAAV production culture), determining the genome titer of the isolated rAA V particles, determining the infectivity of the isolated rAAV particles using a method disclosed herein, and formulating the isolated rAA V particles."
However, para.[0098] only describes "methods for producing a pharmaceutical unit dosage," comprising the steps of isolating particles, determining the genome titer, determining the infectivity, and formulating. It does not disclose how the genome titer and infectivity values are actually used in producing a dosage ꟷ for example, whether the values are incorporated into dosage calculation, selection, or adjustment. Instead, it appears to suggest that performing the steps lead to the intended result of producing a pharmaceutical unit dosage, without specifying any required application of the determined values in dosage formulation.
As such, it is unclear whether the claim requires the values determined in steps b and c to be actually applied in the formulation of the pharmaceutical dosage (and how), or whether it is sufficient that the values are merely determined during a process. It is also unclear whether the AAV particles included in the pharmaceutical unit dosage are from the previously recited compositions, such as the first composition or the reference AAV composition, and, if so, which one.
For the purpose of compact prosecution and applying prior art under 35 USC§ 102 and 103, a prior art method that teaches steps b) and c) in claim 2, and comprising the same four steps for AAV in the "methods for producing a pharmaceutical unit dosage," disclosed in para. [0098] ꟷ namely, isolating AAV particles, determining genome titer, determining the infectivity, and formulating AAV particles ꟷ is considered to meet the limitation "using the AAV genome titer determined in step b) and the relative infectivity determined in step c) to produce a pharmaceutical unit dosage comprising AAV particles."
Claims 9, 11-12, 22, 25, 38 and 71 are rejected for depending from claim 2 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 103 -- New
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.
Claims 2, 9, 11-12, 22, 25 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over François (François et al., Accurate Titration of Infectious AAV Particles Requires Measurement of Biologically Active Vector Genomes and Suitable Controls. Mol Ther Methods Clin Dev. 2018 Jul 27;10:223-236. doi: 10.1016/j.omtm.2018.07.004. PMID: 30112419; PMCID: PMC6090651.; cited in IDS filed 04/14/2021) , in view of
HERMENS (WO2013036118A1- Removal of contaminating viruses from aav preparations; Published on 2013-03-14); as evidenced by
Kotin (Kotin et al. Manufacturing Clinical Grade Recombinant Adeno-Associated Virus Using Invertebrate Cell Lines. Hum Gene Ther. 2017 Apr;28(4):350-360. doi: 10.1089/hum.2017.042. PMID: 28351174);
Zeltner (Zeltner et al. Near-perfect infectivity of wild-type AAV as benchmark for infectivity of recombinant AAV vectors. Gene Ther. 2010 Jul;17(7):872-9. doi: 10.1038/gt.2010.27. Epub 2010 Mar 25. PMID: 20336156; PMCID: PMC2900506);
BIOSTATISTICS (PubH 7405: BIOSTATISTICS METHODS FOR TRANSLATIONAL & CLINICAL RESEARCH; Archived Sept 08, 2017 on WaybackMachine; web.archive.org/web/20170908181957/https://www.biostat.umn.edu/~chap/SS10-Day4-RegApplications-PartC.pdf ); and
Statistical Analysis of Results of Biological Assays and Results. (2008). European Pharmacopoeia. 6th ed. Pp. 571-600).
A) François teaches an improved method of discriminating infectivity in recombinant AAV particles for clinical use , using a non-infectious control (entire document, Abstract for example).
Regarding claim 2, François teaches a method comprising:
a) isolating adeno-associated virus (AAV) particles from a feed comprising an impurity to produce a first composition comprising the isolated AAV particles (page 232, right-hand col, para6, lines 4-6, “AAV8 particles in the culture supernatant were polyethylene glycol (PEG)-precipitated, then purified by double CsCl density gradient ultracentrifugation”);
b) determining the AAV genome titer of the first composition (page 233, left-hand col, “VG Titration by qPCR” VG is vector genome );
c) determining the infectivity of the first composition relative to the infectivity of a reference AAV composition (Table 2; Figure 3); and
d) using the AAV genome titer determined in step b) and the relative infectivity determined in step c) to produce a pharmaceutical unit dosage comprising AAV particles (page 232, right-hand col, para 6; AAV8 particles formulated in 1_ DPBS containing Ca2+ and Mg2+ through dialysis in Slide-A-Lyzer 10K cassettes),
wherein determining the infectivity of the first composition relative to the infectivity of the reference composition comprises
a. preparing serial dilutions of the first composition and the reference AAV composition (Table 2; Figure 3;page 233, right-hand col, para 2, lines 9-12, para 3, lines3-7);
b. inoculating target cells separately with the serial dilutions of the first composition (Table 2; Figure 3, AAV8; page 229, left-hand col, lines21-23, AAV8) and the reference AAV composition(Figure 3, AAV8∆VP1; page 229, left-hand col, lines21-23, AAV8∆VP1);
c. washing the inoculated cells to remove extracellular viral particles (page 229, left-hand col, lines25-26);
d. isolating a first nucleic acid sample and a reference nucleic acid sample from the target cells inoculated with the first composition and the reference AAV composition, respectively (page 234, right-hand col, para 2, lines 1-9);
e. determining the ratio of viral genome copy (VGC) to target cell genome copy (TCGC) in the first nucleic acid sample and the reference nucleic acid sample(page 234, right-hand col, para 2, lines12-27), and
f. calculating the infectivity of the first composition relative to the reference AAV composition (Table 2).
As discussed above, François teaches isolating adeno-associated virus (AAV) particles (page 232, right-hand col, para6), determining AAV genome titer (page 233, left-hand col) and relative infectivity (Table 2; Figure 3), and formulating AAV particles (page 232, right-hand col, para 6). Therefore, François's teachings meet the limitation "using the AAV genome titer determined in step b) and the relative infectivity determined in step c) to produce a pharmaceutical unit dosage comprising AAV particles" based on the current claim interpretation (see section 112(b) above).
However, it should be noted that even under a more narrow claim interpretation, requiring calculating a AAV composition dosage based on the values of AAV genome titer and relative infectivity between AAV composition and a reference AAV, the method in claim 2 is still deemed obvious in view of prior art.
François highlights the need to accurately measure the infectivity of rAAV stocks and the importance of including relevant controls in testing protocols (entire document, see page 224, right-hand col, lines 1-4 for examples).
Although François does not explicitly disclose calculating a dosage comprising AAV particles based on the values of AAV genome titer and relative infectivity between AAV composition and a reference AAV, such practice is strongly implied throughout the reference and is obvious in view of the prior art.
François’s teaching focuses on developing methods to accurately discriminate of infectious and non-infectious vector-containing particles for clinical applications (entire document, see Abstract and discussion for examples) ; and highlights that vector infectivity is critical for the therapeutic efficacy:
“Given that quality attributes of rAAV stocks could be different depending on the manufacturing platform, it is highly important to have accurate analytical methods for their characterization, as emphasized by the FDA.12 Among the quality attributes, the infectious titer is critical to ensure the efficacy of the product.” (page 223, right-hand col, para 3).
Thus, it is evident from François’s teaching that its methods are specifically intended for the quality assessment of clinical grade Recombinant AAV pharmaceutical products.
A skilled artisan would recognize that clinical grade AAV products have dosage and efficacy requirements. Pharmaceutical products generally involve a pre-determined dosage range. For example, Kotin (cited by François as Ref. 7) describes single patient dosages in the range from ≤1E + 12 to ≥1E + 16 particles or vg, vector genome–containing particles (page 352, left-hand col, para 2, lines 8-10). Given the critical role of infectivity in efficacy, a skilled artisan would understand that determining dosage for clinical use must consider not only viral genome titer but also infectivity (i.e., the number of biologically active particles).
A composition comprising the same genome titer but lower infectivity would not be expected to yield the same therapeutic effect as one with higher infectivity (see Table 2 and Fig 3 in François, AAV 8 vs. AAV8∆VP1 for examples ). Zeltner supports this rationale, stating that vectors with superior infectivity enable lower dosing to "achieve therapeutic efficacy, thereby minimizing the risk of an adverse immune response.” (page 2, para 2)
Therefore, it would have been prima facie obvious to one of ordinary skill in the field of gene therapy to consider both genome titer and relative infectivity between the AAV composition and a reference AAV when producing a dosage for clinical treatment.
François further suggests as part of background for the field of viral vector production for gene therapy, the use of insect cells and baculoviruses is highly convenient for industrial manufacturing (page 223, right-hand col, lines16-17). While François teaches calculating the infectivity of the test composition and the reference composition (Table 2), it does not explicitly teach using a parallel-line model for such calculation.
The parallel-line method is a well-known robust biostatistical analysis method for comparing one or more test substances against a reference substance based on their relative potency, according to Applicant’s own disclosure and existing knowledge in the field (see specification, page 23, lines11-15; also see Statistical Analysis of Results of Biological Assays and Results. (2008). European Pharmacopoeia. 6th ed. Pp. 571-600).
B) HERMENS teaches a method of producing and purifying recombinant AAV for gene therapy in insect cells using a baculovirus-based expression system (entire document, page 7 "Detailed description of the invention" for example).
Regarding claim 2, HERMENS teaches calculating the infectivity of the test composition relative to the reference composition using a parallel-line model (page 22, lines12-14), to test serial dilutions of the test sample against the reference standard.
C) It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method for measuring viral particle infectivity taught by François with the statistical calculation method using a parallel-line model from HERMENS because both references are in the same field of viral vector production for gene therapy. François focuses on the measurement of infectivity using biological activity, while HERMENS provides a specific statistical approach to calculate infectivity, enhancing the capability for relative comparison of such measurements between the test and reference group for each serial dilution.
The person of ordinary skill would have had a reasonable expectation of success in applying the parallel-line model from HERMENS to the method of François because HERMENS 's model offers a known and accepted method for analyzing biological data (See Statistical Analysis of Results of Biological Assays and Results. (2008). European Pharmacopoeia. 6th ed. Pp. 571-600). This statistical model is well-established in comparing test and reference groups, making it appropriate, technically applicable, and obvious to use for the infectivity assessment biological assay described in François.
The skilled artisan would have been motivated to integrate these teachings to obtain the predictable result of precise and reliable infectivity measurements, which is critical in the context of viral vector production for gene therapy. This motivation is further supported by François's highlight on the convenience of using insect cells and baculovirus-based expression system, which directly aligns with the system used in HERMENS, suggesting a shared technological basis and reinforcing the practical benefits of combing these methods.
Therefore, it would have been obvious to employ the parallel-line model of HERMENS in the viral infectivity measurement process of François, representing a predictable use of prior art element according to a known method to yield predictable results (See MPEP §2143).
C) Regarding claim 9, François teaches calculating VGC:TCGC ratio for each dilution of test and reference composition (page 234, right-hand col, para 2, lines12-27).
HERMENS inherently teach the plotting, fitting, and calculating steps in claim 9 by teaching using parallel-line model (page 22, lines12-14). As evidenced by BIOSTATISTICS, parallel-line model comprises plotting log values of test and reference group (slide 9, 15; 3-4); fitting the test and reference data points to a test and reference line using a common slope (slides 15-16); and calculating the infectivity of the test composition relative to the reference composition as antilog
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(slides 11-12).
Regarding claim 11, François teaches incubating the target cells in the presence of viral particles for about 24 hours (page 228, left-hand col, para3, lines 1-3; page 225, right-hand col, para2, line18; page 234, left-hand col, para2, line 4).
Regarding claim 12, François teaches polymerase chain reaction(page 234, right-hand col, para 2, lines12-27, TaqMan qPCR).
Regarding claim 22, François teaches BHK21 and HEK293 (page 223, right-hand col, lines 14-20).
Regarding claim 25, François teaches the first composition and the reference composition have a different titer, wherein the titer is measured as genome copy (GC) per milliliter (Table 1).
Regarding claim 71, François teaches the AAV comprises a capsid protein AAV8 serotype (entire document, abstract for example).
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over François in view of HERMENS, as applied to claims 1 and 12 above and further in view of Huijsmans (Huijsmans et al. , Sensitive detection and quantification of the JAK2V617F allele by real-time PCR blocking wild-type amplification by using a peptide nucleic acid oligonucleotide. J Mol Diagn. 2011 Sep;13(5):558-64. doi: 10.1016/j.jmoldx.2011.04.002. Epub 2011 Jun 30. PMID: 21723417; PMCID: PMC3157608.)
A) The teachings of François and HERMENS are recited above and applied as for base claims 1 and 12.
Regarding claim 38, while François and HERMENS both teach PCR (François et al., page 234, right-hand col, para 2, lines12-27; HERMENS, page 22, line 8) with primers, and François further teaches using PCR primers and probes to detect albumin DNA sequence for determining target cell genome copy (page 234, right-hand col, para 2, lines12-27), these references do not specifically teach primers comprise any of the sequences required in claim 38.
B) Huijsmans teaches a method for detection and quantification of gene targets using PCR (entire document).
Regarding claim 38, Huijsmans teaches a combination of a probe, forward primer, and reverse primer for detecting albumin DNA, comprise a polynucleotide consisting of the nucleotide sequence of SEQ ID NO: 4 (Table 2, Albumin forward primer, 5-TGAAACATACGTTCCCAAAGAGTTT-3), 5 (Table 2, Albumin reverse primer, 5-CTCTCCTTCTCAGAAAGTGTGCATAT-3), and 6 (Table 2, Albumin probe, 5-FAM-TGCTGAAACATTCACCTTCCATGCAGA-TAMRA-3).
C) It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the PCR primers and probe taught in Huijsmans for those used in the PCR of the combined methods of François and HERMENS, because all three references are within the same field of molecular biology, specifically using PCR techniques to detect and quantify target DNA sequences.
Specifically, Huijsmans and François share commonality of using PCR for detecting albumin gene DNA, highlighting their technical compatibility.
This substitution is a predictable use of known primer and probes within the same category -- PCR for DNA detection -- with no unexpected change in function or result. Since Huijsmans and François both use PCR to detect the same albumin gene target, using the primers and probe from Huijsmans in the context of François's method would not alter the fundamental operation of PCR but would utilize a variant of the same technology, yielding the same predictable result of accurate detection and quantification of albumin gene copies.
Therefore, it would have been obvious to use the specific set of probe and primers for detecting albumin DNA as taught by Huijsmans in the PCR method to detect albumin DNA gene copies, according to the combined teachings of François and HERMENS, representing a simple substitution of one known element for another to obtain predictable results, see MPEP §2143.
Conclusion
No claims are allowed.
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/TIAN NMN YU/
Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Any quantity can be a pre-determined quantity.