DETAILED ACTION
Disposition of Claims
Claims 96-118 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240393222A1, Published 11/28/2024.
It is noted that four pending IPR are noted in parent applications (IPR2023-01044; IPR2023-01045; IPR2023-00149; and IPR2023-00150). Documents from these IPR appear to have been included on the IDSes noted herein.
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Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/12/2025 and 08/07/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of legal phraseology (the term “e.g.” stands for “exepli gratia” and can be replaced instead with “for example”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 96-102 and 104 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.
Claim 96 recites that the heterogeneous mixture comprises rAAV particles with full viral genomes, rAAV particles with fragmented genomes, and rAAV particles without genomes, and further recites that each distinct sedimenting boundary corresponds to a resolvable species of rAAV viral particle. However, step (iii) requires “determining the genome size of the resolvable species of rAAV viral particles.” It is unclear how the genome size is to be determined for a resolvable species comprising rAAV particles without genomes, or whether the phrase “the resolvable species” is intended to exclude the genome-free particle species. Accordingly, the scope of the required genome-size determination is unclear.
Claims 97-102 are also rejected for depending upon claim 96, but not clarifying the issues of claim 96. Claim 104 is rejected for a similar reason as it depends upon claim 103, but claim 103 expressly requires the heterogeneous mixture to comprise rAAV particles without genomes.
Claim 97 is 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.
Claim 97 recites the limitation " the sedimentation coefficients" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 96 recites measuring the rate of movement or migration of sedimenting boundaries but does not previously recite determining or otherwise identify “sedimentation coefficients” of the rAAV particles.
For at least these reasons, the metes and bounds of the claim are unclear.
Claims 98-100, 105-107, and 113-115 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.
Claim 96 recites subjecting the heterogeneous mixture to “boundary sedimentation velocity analytical ultracentrifugation,” but does not separately introduce “a boundary sedimentation velocity” as an operation or parameter. Accordingly, it is unclear what is referenced by “the boundary sedimentation velocity” in claim 98 and what, specifically, is required to be performed at about 3,000 rpm to about 20,000 rpm.
Claims 99-100, 105-107, and 113-115 are rejected for similar reasoning.
For at least these reasons, the metes and bounds of instant claims 98-100, 105-107, and 113-115 are unclear.
Claims 98-101, 105-109, 111, and 113-116 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.
The term “about” in claims 98-101, 105-109, 111, and 113-116 is a relative term which renders the claim indefinite. The term “about” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. At ¶[0083] in the specification, a definition for “about” is provided, but it fails to establish a numerical measurement for this relative term (e.g. “about” means +/- 10% of the measurement claimed, etc.) As a specific, measurable amount for what is, and what is not, intended by the term “about” is not provided, the claims are rejected for being indefinite.
For at least these reasons, the metes and bounds of instant claims 98-101, 105-109, 111, and 113-116 are unclear.
Claims 102, 110, 111, and 117 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.
The claims recite a “total concentration” of rAAV viral particles in units of vector genomes per milliliter (vg/mL). However, the heterogeneous mixtures recited in the respective independent claims expressly comprise rAAV particles without a genome in addition to genome-containing rAAV particles. Accordingly, it is unclear how the “total concentration” of viral particles, including genome-free particles, can be expressed in units of vg/mL, which measures vector genomes rather than total physical particles. It is therefore unclear whether the claimed concentration refers to the concentration of all rAAV particles in the mixture, only genome-containing rAAV particles, or the vector-genome titer of the preparation.
For at least these reasons, the metes and bounds of instant claims 102, 110-111, and 117 are unclear.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 96 is drawn to a method of quantifying recombinant adeno-associated viral (rAAV) particles with full viral genomes in a heterogeneous mixture of rAAV viral particles, the heterogeneous mixture comprising species of rAAV viral particles including rAAV viral particles with full viral genomes, rAAV viral particles with fragmented genomes, and rAAV viral particles without genome, said method comprising:
(i) subjecting the heterogeneous mixture of rAAV viral particles to analytical ultracentrifugation under boundary sedimentation velocity conditions to generate sedimenting boundaries;
(ii) measuring the rate of movement or migration of the sedimenting boundaries, wherein movement or migration of each species of rAAV viral particles in the heterogeneous mixture of rAAV viral particles results in distinct sedimenting boundaries, each distinct sedimenting boundary corresponding to a resolvable species of rAAV viral particle;
(iii) determining the genome size of the resolvable species of rAAV viral particles in the heterogeneous mixture of rAAV viral particles; and
(iv) determining the quantity of the rAAV viral particles in the heterogenous mixture of rAAV viral particles with full viral genomes.
Further limitations on the method of claim 96 are wherein step (iii) comprises comparing the sedimentation coefficients of the rAAV viral particles with a standard curve generated by sedimentation coefficients of rAAV viral particles comprising rAAV genomes of known nucleotide sizes (claim 97); wherein the boundary sedimentation velocity is from about 3,000 rpm to about 20,000 rpm (claim 98); wherein the boundary sedimentation velocity is from about 10,000 rpm to about 20,000 rpm (claim 99); wherein the boundary sedimentation velocity is from about 15,000 rpm to about 20,000 rpm (claim 100); wherein the boundary sedimentation is performed at a temperature of about 4°C (claim 101); and wherein the total concentration of rAAV viral particles in the heterogeneous mixture of rAAV viral particles prior to step (i) is greater than 5x1011 vg/mL (claim 102).
Claim 103 is drawn to a method of determining the percent of recombinant adeno-associated viral (rAAV) particles with full viral genomes in a heterogeneous mixture of rAAV viral particles, the heterogeneous mixture comprising species of rAAV viral particles including rAAV particles with full viral genomes, rAAV viral particles with fragmented genomes, and rAAV viral particles without genome, said method comprising:
(i) subjecting the heterogeneous mixture of rAAV viral particles to analytical ultracentrifugation (AUC) under boundary sedimentation velocity conditions to generate sedimenting boundaries;
(ii) measuring the rate of movement or migration of the sedimenting boundaries, wherein movement or migration of each species of rAAV viral particles in the heterogeneous mixture of rAAV viral particles results in distinct sedimenting boundaries, each distinct sedimenting boundary corresponding to a resolvable species of rAAV viral particle;
(iii) determining the molar concentration of each resolvable species in the heterogeneous mixture of rAAV viral particles; and
(iv) determining the percent of rAAV viral particles with full viral genomes in the heterogeneous mixture of rAAV viral particles.
Further limitations on the method of claim 103 are wherein the method is further comprising determining the genome size of each resolvable species of rAAV viral particles after step (ii) and prior to step (iii)(claim 104); wherein the boundary sedimentation velocity is from about 3,000 rpm to about 20,000 rpm (claim 105); wherein the boundary sedimentation velocity is from about 10,000 rpm to about 20,000 rpm (claim 106); wherein the boundary sedimentation velocity is from about 15,000 rpm to about 20,000 rpm (claim 107); wherein the boundary sedimentation is performed at a temperature of about 4°C (claim 108); wherein the centrifugation is run from about 0.5 hours to about 2 hours (claim 109); wherein the total concentration of rAAV viral particles in the heterogeneous mixture prior to step (i) is greater than 5x1011 vg/mL (claim 110); and wherein the total concentration of rAAV viral particles in the heterogeneous mixture prior to step (i) is from about 1x1011 vg/mL to about 1x1013vg/mL (claim 111).
Claim 112 is drawn to a method of measuring the relative amount of recombinant adeno-associated viral (rAAV) particles with full vector genomes in a heterogeneous mixture of rAAV viral particles, the heterogeneous mixture comprising species of rAAV viral particles including rAAV particles with full viral genomes, rAAV viral particles with fragmented genomes, and rAAV viral particles without genome, said method comprising:
(i) subjecting the heterogeneous mixture of rAAV particles to analytical ultracentrifugation under boundary sedimentation velocity conditions wherein the sedimentation of rAAV particles is monitored at time intervals;
(ii) plotting the differential sedimentation coefficient distribution value (C(s)) versus the sedimentation coefficient in Svedberg units (S);
(iii) integrating the area under each peak in the C(s) distribution to determine the relative concentration of each species of rAAV particles in units of detection;
(iv) determining the relative amounts of each rAAV particle species in the heterogeneous mixture of rAAV particles; and
(v) comparing the amount of rAAV particles having an S value that corresponds to rAAV particles with full vector genomes to the amount of rAAV particles having an S value that does not correspond to rAAV particles with full vector genomes or to the total amount of rAAV particles in the preparation to thereby measure the relative amount of rAAV particles with full vector genomes in the heterogeneous mixture of rAAV particles.
Further limitations on the method of claim 112 are wherein the boundary sedimentation velocity is from about 3,000 rpm to about 20,000 rpm (claim 113); wherein the boundary sedimentation velocity is from about 10,000 rpm to about 20,000 rpm (claim 114); wherein the boundary sedimentation velocity is from about 15,000 rpm to about 20,000 rpm (claim 115); wherein the boundary sedimentation is performed at a temperature of about 4°C (claim 116); and wherein the total concentration of viral particles in the heterogeneous mixture of viral particles prior to step (i) is greater than 5x1011 vg/mL (claim 117).
Claim 118 is drawn to a method of measuring the relative amount of rAAV particles with full vector genomes in a heterogeneous mixture of rAAV particles, the method comprising removing a sample of the rAAV particles from the heterogeneous mixture of rAAV particles following one or more steps in the purification process, and measuring the relative amount of rAAV particles with full vector genomes according to the method of claim 117.
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 96-118 are rejected under 35 U.S.C. 103 as being unpatentable over Le Bec et. al. (WO2014125101A1, Pub. 08/21/2014; CITED ART OF RECORD; hereafter “Le Bec”) in view of de la Maza et. al. (de la Maza and Carter, “DNA Structure of Incomplete Adeno-Associated-Virus Particles” in REPLICATION OF MAMMALIAN PARVOVIRUSES (Ward, D., and Tattersall, P., eds.), Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 193-204 (1978).; hereafter “de la Maza”); Cole et. al. (Cole JL, et. al. Methods Cell Biol. 2008;84:143-79.; CITED ART OF RECORD; hereafter “Cole”); Sommer et. al. (Sommer JM, et. al. Mol Ther. 2003 Jan;7(1):122-8.; CITED ART OF RECORD; hereafter “Sommer”); and Bleker et. al. (Bleker S, et. al. J Virol. 2005 Feb;79(4):2528-40.; hereafter “Bleker”.)
The Prior Art
Le Bec teaches analytical ultracentrifugation (AUC) on adeno-associated virus (AAV) in real time in order to produce sufficient amounts of purified AAV product for therapeutic applications such as gene therapy and/or DNA vaccination, in uses during clinical or commercial trials (entire document; see abstract.) Le Bec teaches characterization and quantification of recombinant AAV particle populations in purified rAAV preparations by AUC. In particular, Le Bec determines the sedimentation coefficients of different AAV particle populations by centrifugation in real time, follows the sedimentation by absorbance, and obtains the sedimentation coefficients of the different populations via SEDFIT. Le Bec further teaches that the resulting distribution profile distinguishes empty rAAV particles at approximately 65S from genome-containing rAAV particles between approximately 80S and 110S, including particles containing single-stranded genome at approximately 90S and double-stranded genome at approximately 105S. Le Bec expressly states that the AUC method permits separation and quantification of different species present in an AAV preparation and reports relative amounts of genome-containing particles in the analyzed preparations. Le Bec further cautions that the particular sedimentation values are vector-specific and will be redefined according to genome type. (section d) “Analysis of empty and solid AAV viral particles: Analytical ultracentrifugation”, particularly the discussion corresponding to Figs. 2-3.) Le Bec teaches performing the AUC at 16,000 rpm, which falls within each of the claimed ranges of about 3,000-20,000 rpm, about 10,000-20,000 rpm, and about 15,000-20,000 rpm (discussion corresponding to Figs. 2-3; instant claims 98-100, 105-107, 113-115.) Le Bec teaches that the samples are loaded at 5x10^9 and 10^10 vg, wherein the starting concentrations obtained from cell culture purifications are between 1.2x10^10 vg/mL to 6.4 x10^10 vg/mL (Table 1), with the amount of virus obtained after purification being between 5.1 x10^11 to 1.6x10^12 vg/mL (Table 2).
While Le Bec teaches rAAV preparations which contain distinguishable particle species, subjecting the preparation to AUC, monitoring sedimentation of the particle populations, resolving particle species according to their sedimenting behavior, and determining the quantity of genome-containing rAAV particles, Le Bec does not expressly disclose that the heterogeneous rAAV preparation includes particles containing fragmented genomes, nor does Le Bec expressly determine the genome size of such fragmented genome species. However, such modifications would be obvious to a skilled artisan, given the teachings of de la Maza, Cole, Blecker, and Sommer.
De la Maza teaches that AAV preparations were known to contain incomplete AAV particles carrying incomplete or variant viral genomes (pp. 193-204). De la Maza notes the “light” particles are AAV which are either empty or contain DNA of less than full genome length (p. 193, ¶1), and that all density classes of AAV virions appear to contain varying proportions of incomplete genomes (p. 193, ¶2). De la Maza provides different sedimentation coefficients of these different populations of AAV particles (Table 1).
Cole further teaches the principles and conventional analysis of sedimentation-velocity(SV) AUC (pp. 145-7). Cole teaches that an SV experiment monitors the rate at which molecular boundaries move during centrifugation and defines the sedimentation coefficient as the velocity of the particle relative to the applied centrifugal field (p. 146, ¶1 to p. 147, ¶1). Cole further teaches that the sedimentation coefficient is proportional to buoyant molar mass and inversely proportional to frictional coefficient and that monitoring boundary motion permits determination of sedimentation coefficients (pp. 146-7, ¶ bridging pages). Cole additionally teaches determining sedimentation coefficient distributions, including c(s), for heterogeneous preparations and explains that relationships between sedimentation coefficient and mass can be used to identify peaks corresponding to fragments (p. 148). Cole further teaches that SEDFIT implements c(s) analysis by fitting sedimentation boundaries to Lamm equation solutions to determine the concentration associated with each species and that, for mixtures, the analysis seeks the concentration, sedimentation coefficient, and mass of individual species (pp. 165-6). Cole teaches the AUC equipment used in their testing had an operating range of 0-40 deg C, with the unit having a difficult time maintaining temperatures below 4 deg C (pp. 163-4, ¶ bridging pages.)
Sommer teaches that determining the amounts of genome-containing and empty AAV particles was a known and useful analytical objective for recombinant AAV preparations (entire document; see abstract.) Sommer teaches determination of both vector genome and capsid particle titers, and calculates the ratio of empty to full particles in purified AAV vector preparations (abstract; pp. 124-5, Figs. 2-4, Table 1). Sommer teaches purified rAAV preparations having vector-genome concentrations that overlap and exceed the claimed concentration of greater than 5x10^11 vg/mL as required by instant claims 102, 110-111, and 117. Sommer reports eight AAV-hFIX16 preparations having titers ranging from approximately 4.6x10^11 to 1x10^13 vg/mL (p. 124, Fig. 2; Table 1).
Sommer also teaches the use of a calibration relationship to determine an unknown compositional property of an AAV preparation from a measurable physical property of the AAV particles. In particular, Sommer calculates a predicted relationship between the capsid-to-vector genome ratio (cp/vg) and the measured A260/A280 absorbance ratio for recombinant AAV-hFIX16, plotting predicted A260/A280 values over cp/vg ratios ranging from 1, representing no empty capsids, to 50, representing approximately 98% empty capsids (p. 125, Fig. 3). Sommer then validates use of that relationship by comparing cp/vg ratios determined from absorbance measurements with cp/vg ratios independently determined by qPCR and capsid ELISA for eight rAAV samples (p. 125, Fig. 4; pp. 124-5). A skilled artisan would find instant claim 97 obvious, as they would have a reasonable expectation that such an empirical calculation would be useful because Le Bec had already demonstrated reproducible, genome-dependent differences in the sedimentation coefficients of rAAV particles, while Sommer demonstrated that vector specific calibration relationships could successfully be used to quantitatively infer AAV composition from a measured physical parameter.
Bleker teaches loading AAV2 particles on a 10-30% sucrose gradient and centrifugation for 160,000xg for 2 h at 4 deg. C (p. 2530, “Materials and Methods: Continuous sucrose gradient.”) Bleker teaches the ultracentrifugation allows them to distinguish among DNA-containing, empty, and dissociated particles sedimenting at 110S, at 60S, and below 20S (p. 2533, rt. Col. ¶2). Although Bleker employs preparative sucrose-gradient ultracentrifugation rather than analytical ultracentrifugation, Le Bec teaches the use of AUC to resolve rAAV populations according to differences in sedimentation behavior. Therefore, the limitations of instant claims 101, 108-109, and 116 would be obvious to a skilled artisan.
Given the combined teachings of Le Bec in view of Cole, Sommer, Bleker, and de la Maza, the instantly claimed invention would have been obvious to a skilled artisan. Le Bec teaches use of AUC and SEDFIT to resolve and quantify distinct rAAV particle populations based on their sedimentation behavior, including empty and genome-containing particles having different sedimentation coefficients. De la Maza further establishes that AAV preparations contain incomplete particles having fragmented or otherwise incomplete encapsidated genomes of differing lengths. Cole teaches the conventional use of sedimentation velocity (SV) AUC to monitor movement of sedimenting boundaries, determine sedimentation coefficient distributions, including c(s) distributions, resolve heterogeneous species, and quantitatively determine the concentration of resolved species, including by integration of the resulting distributions. Sommer independently teaches that quantification of full and empty rAAV particles, including determination of capsid-to-vector genome ratios and the relative proportion of genome-containing particles, was a recognized AAV quality control objective and further demonstrates the use of quantitative calibration relationships to infer AAV composition from measured analytical parameters. Bleker additionally teaches sedimentation-based separation of AAV2 particles under specific ultracentrifugation temperature and time conditions, and noting the difference in sedimentation of full and empty AAV particles, thereby establishing that AAV full/genome-containing and empty particle populations were known to remain distinguishable under lower temperature centrifugation conditions and over run times within the presently claimed ranges. Accordingly, one of ordinary skill in the art would have had reason to apply the quantitative SV-AUC methods of Cole to the heterogeneous rAAV preparations taught by Le Bec and de la Maza to resolve full-genome, fragmented-genome, and empty particle populations, and determine the amount, molar concentration, or relative percentage of the full-genome populations as recited in instant claims 96, 103, and 112, while employing conventional AAV centrifugation conditions such as those taught by Bleker. It would have been further obvious to apply the same analysis to samples obtained following purification, as recited in instant claim 118, in order to assess changes in the relative amount of full-genome rAAV particles and thereby evaluate the quality of the purified vector preparation.
It would have been obvious to one of ordinary skill in the art to modify the methods taught by Le Bec in order to determine the presence, amount, and size of fragmented genomes in a heterogeneous rAAV preparation, thereby providing a method for subjecting rAAV preparations to AUC and resolving all particle species according to their sedimenting behavior. One would have been motivated to do so, given the suggestion by Cole that the principles of SV-AUC were well known in the art at the time of the instant claims, and their application to separation of viruses was suggested by Cole. There would have been a reasonable expectation of success, given the knowledge that Sommer teaches the quantification of full and empty AAV particles and given that de la Maza teaches that there can also be fragmented genomes that can be resolved as well, and also given the knowledge that general parameters for temperature and time for running ultracentrifugations were known in the art, as taught by Bleker. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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 96-118 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 12,013,326. Both sets of claims are drawn to methods of determining the molar concentrations of one or more species of individual variant viral particles comprising fragmented recombinant adeno-associated viral (rAAV) genomes in a heterogeneous mixture of viral particles, and both sets of claims are drawn to determining the size of one or more fragmented genomes in said composition. Both sets of claims are drawn to the boundary sedimentation velocities being between 3k-20k rpm, both sets of claims are drawn to the measurement of the rate or movement of the sedimenting boundaries and determining the genome size and quantity of the species. Both claim the AUC is performed at 4 deg C for 0.5 to about 2 hours. Both claim the total concentration of viral particles in the heterogeneous mixture of viral particles prior to the separation step is greater than 5×1011 vg/mL. Both claim generation of standard curves to determine the viral particle compositions. Both claim determining the relative amount of each species within the heterogeneous mixtures.
Therefore, the instant claims and the ‘326 claims are not patentably distinct.
Claims 96-118 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 12,031,894. Both sets of claims are drawn to methods of quantifying one or more species of individual variant viral particles comprising fragmented recombinant adeno-associated viral (rAAV) genomes in a heterogeneous mixture of viral particles. Both sets of claims are drawn to the boundary sedimentation velocities being between 3k-20k rpm, both sets of claims are drawn to the measurement of the rate or movement of the sedimenting boundaries and determining the genome size and quantity of the species. Both claim the AUC is performed at 4 deg C for 0.5 to about 2 hours. Both claim the total concentration of viral particles in the heterogeneous mixture of viral particles prior to the separation step is greater than 5×1011 vg/mL. Both claim generation of standard curves to determine the viral particle compositions. The main difference between the two sets of claims is that the reference claims do not specifically provide for determining the relative amount of full genomes in the heterogeneous composition, although the determination of the quantity of “one or more species” would inherently comprise such a task in the method of the reference claims.
Therefore, the instant claims and the ‘894 claims are not patentably distinct.
Claims 96-118 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-34 of U.S. Patent No. 10,429,288 in view of Bleker (supra). Both sets of claims are drawn to methods of determining the molar concentrations of one or more species of individual variant viral particles comprising fragmented recombinant adeno-associated viral (rAAV) genomes in a heterogeneous mixture of viral particles, and both sets of claims are drawn to determining the size of one or more fragmented genomes in said composition. Both sets of claims are drawn to the boundary sedimentation velocities being between 3k-20k rpm, both sets of claims are drawn to the measurement of the rate or movement of the sedimenting boundaries and determining the genome size and quantity of the species. Both claim generation of standard curves to determine the viral particle compositions. Both claim determining the relative amount of each species within the heterogeneous mixtures.
The main difference is that the instant claims provide for performing the AUC at 4 deg C for 0.5 to about 2 hours and the total concentration of viral particles in the heterogeneous mixture of viral particles prior to the separation step is greater than 5×1011 vg/mL. However, such a difference would be obvious, given the art as taught by Bleker (detailed supra).
Therefore, the instant claims and the ‘288 claims are not patentably distinct, especially in view of Bleker.
Conclusion
No claims are allowed.
The art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
US20220275358A1. Post-filing art that teaches AUC can determine empty/full AAV capsid ratios and can resolve AAV vectors having fragmented genomes.
US20230374468A1. Post-filing art that teaches AUC can determine empty/full AAV capsid ratios and can resolve AAV vectors having different genome sizes.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
