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
Claims 62-64, 66, and 68-82 are pending and under examination on their merits. Claims 1-61, 65, and 67 are cancelled.
Response to Arguments
Applicant's arguments filed 12/17/2025 have been fully considered but they are not persuasive. Applicant argues against the rejection of claims under 35 U.S.C. 103 over Adie in view of Takara on the grounds that Adie is drawn to the purification of nucleic acids rather than a non-enveloped virus. Applicant argues that the use of chaotropic agents and proteases disrupt macromolecules, including viral capsid and protein machinery in order to generate purified nucleic acid free of viral capsid and other viral components (Arguments, paragraph 1 on page 6).
In response, Applicant has not given the term “virus” its broadest reasonable interpretation. The claims do not require, excluding newly added claims 70 and 74-75, that the virus is the complete, infectious, extracellular form consisting of genetic material inside a protective protein shell (capsid). For example, the claims do not recite “viral particle” or “virion.” Adie teaches purifying the nucleic acid derived from a hepatitis A virus (Adie claim 23), which is a non-enveloped virus as evidenced by CDC (“Infectious Agent,” last line on page 1). Thus, Adie teaches purifying a virus, although Adie does not teach purifying a viral particle or virion.
Applicant’s arguments pertaining to the use of the term “polidodecanol” are persuasive. However, the specification also contains a trademark (see objection below) so the specification is objected to in this action as well.
Specification
The use of the term “Capto” AVB, 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. See the specification line 12 on page 36.
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.
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.
(New Rejection Necessitated by the Amendment) Claims 76-82 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 76 is indefinite for “from about 0.1% to about 2% (w/v) Laureth-9” because it is unclear whether the units in parenthesis are merely exemplary or required.
Claims 77-82 are rejected for depending from a rejected based claim and not rectifying the source of indefiniteness described above.
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.
(New Rejection Necessitated by Amendment) Claims 76 and 78-79 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Per MPEP 2164.01(a), the following eight factors should be considered when determining whether the person of ordinary skill in the art would face undue experimentation to make and/or use the invention: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
Nature of the invention. Claim 76 is drawn to a method of purifying a non-enveloped virus comprising loading a mixture comprising the non-enveloped virus onto a chromatography support, washing the chromatography support with a wash solution comprising from about 0.1% to about 2% Laureth-9, and eluting the non-enveloped virus from the chromatography support to obtain a purified eluate comprising the non-enveloped virus. Claim 78 recites chromatography comprises affinity chromatography and claim 79 recites that the affinity chromatography is selected from protein A chromatography, protein G chromatography, or protein L chromatography.
Breadth of the claims. Claims 78-79 are interpreted as limiting the chromatography support in claim 76. Thus, claim 78 is drawn to a method of purifying a non-enveloped virus comprising loading a mixture comprising the non-enveloped virus onto an affinity chromatography support and claim 79 is drawn to a method of purifying a non-enveloped virus comprising loading a mixture comprising the non-enveloped virus onto a protein A, protein G, or protein L chromatography support.
State of the prior art and unpredictability. Wang et al. (Mol Ther Methods Clin Dev. 2015 Nov 4;2:15040) teaches that various ligands have been used for affinity chromatography purification of AAV including heparin, mucin, A20 monoclonal antibody, and AVB Sepharose High Performance (Introduction, page 1, paragraph bridging left and right column). The ligand of the AVB resin is a single-chain Llama antibody produced from yeast which is conjugated to Sepharose beads (Introduction, right column, paragraph 2).
In contrast, Grodzki et al. (2010, Antibody Purification: Affinity Chromatography – Protein A and Protein G Sepharose. In: Oliver, C., Jamur, M. (eds) Immunocytochemical Methods and Protocols. Methods in Molecular Biology, vol 588. Humana Press) teaches that the purification of immunoglobins (namely IgG, IgG fragments and subclasses) use the high affinity of protein A and protein G for the Fc region of polyclonal and monoclonal IgG-type antibodies (page 34, paragraph 4).
Guidance in the specification and working examples. The specification provides no working examples of loading a protein G, protein A, or protein L chromatography support with a non-enveloped virus. Rather, the specification discloses loading Capto® AVB resin with AAV (see example 3 on page 36, bottom paragraph).
Amount of experimentation necessary. The person of ordinary skill in the art would have faced undue experimentation in order to practice the invention as claimed because protein A, protein G, and protein L chromatography columns bind to antibodies or antibody fragments, not non-enveloped viruses. Although affinity chromatography supports for non-enveloped viruses are taught by the prior art, these supports do not include protein A, protein G, or protein L.
Taking these factors into account, undue experimentation would be required by one of ordinary skill in the art to practice the full scope of the claimed invention. Thus, the claims are not fully enabled by the disclosure.
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.
The following rejections are necessitated by the amendment.
Claims 62-64, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Adie (US 2012/0100599 A1; IDS 7/14/2023) in view of Takara (US 2018/0273907 A1; IDS 7/14/2023) and as evidenced by CDC (2025, website).
Adie teaches a method of purifying a nucleic acid in a biological sample (“mixture”) comprising incubating the biological sample in the presence of 0.5 to 5% V/V polidocanol (Abstract and Adie claim 16). Adie teaches other names for the compound termed “polidocanol” including laureth-9 ([0033]). Incubating the mixture with polidocanol necessarily requires contacting the mixture with polidocanol. The biological sample comprises chemical compounds such as haptens, antigens, and antibodies ([0075]), which are impurities because they are not nucleic acids and are thus not purified. The nucleic acid binds to a binding material during the incubation and is optionally washed (Adie claim 18).
Adie teaches purifying the nucleic acid derived from a hepatitis A virus (Adie claim 23), which is a non-enveloped virus as evidenced by CDC (“Infectious Agent,” last line on page 1).
Regarding claim 62, Adie does not teach filtering the mixture comprising the non-enveloped virus.
Regarding claim 63, Adie does not teach that the filtering comprises ultrafiltration.
Regarding claim 64, Adie does not teach that the filtering is performed after contacting the mixture with the solution comprising Laureth-9.
Takara teaches purifying a non-enveloped virus by ultrafiltration ([0064]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add an ultrafiltration step before or after Adie’s step of incubating the sample with polidocanol in order to further purify the hepatitis A virus (“non-enveloped virus”). The person of ordinary skill in the art would have had a reasonable expectation of success in the addition of a filtration step to further purify Adie’s hepatitis A virus.
Regarding claim 66, Adie teaches that the solution comprises 0.5 to 5% v/v polidocanol (Abstract), which overlaps with 0.1% to about 2% Laureth-9.
New claims 68-69 are rejected under 35 U.S.C. 103 as being unpatentable over Adie (US 2012/0100599 A1; in IDS 7/14/2023) in view of Takara (US 2018/0273907 A1; in IDS 7/14/2023) and as evidenced by CDC (2025, website), as applied to claims 62-64 and 66 above, further evidenced by addGene (2025 website).
See discussion of Takara and Adie above, which is incorporated into this rejection as well.
Regarding claim 68, Adie does not teach that the non-enveloped virus is AAV.
However, Takara teaches that AAV has clinical relevance as a vector for gene transfer used in gene therapy for the treatment of congenital genetic disease as well as the treatment of cancer or infection ([0003]). AAV is a non-enveloped virus as evidenced by addGene (paragraph 1 on page 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to replace Adie’s nucleic acid derived from a hepatitis A virus with Takara’s rAAV. The person of ordinary skill in the art would have been motivated to purify AAV for use in gene therapy. The person of ordinary skill in the art would have had a reasonable expectation of success given that Adie’s method purifies hepatitis A, which is also a non-enveloped virus.
Regarding claim 69, Adie does not teach the concentration of virus in VG/mL. However, Adie teaches eluting bound DNA with an elution buffer ([0070]).
Takara teaches a genomic titer of recombinant AAV in units of VG/mL ([0083]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of elution buffer in the method of Adie modified by Takara. The person of ordinary skill in the art would have had a reasonable expectation in the optimization because concentration is a results-effective variable: eluting with a larger volume results in lower concentrations of DNA (i.e. genomic copies of virus) and elution with smaller volume results in higher concentration of DNA.
New claims 69-78 and 80-82 are rejected under 35 U.S.C. 103 as being unpatentable over Kaspar (WO 2019/094253 A1) in view of Kondratova et al. (Molecular Therapy Methods & Clinical Development 15 (2019): 112-119) and Adie (US 2012/0100599 A1; in IDS 7/14/2023) as evidenced by addGene (2025, website) and by CDC (2025, website).
Regarding claims 76-78, Kaspar teaches a method for the purification of a sample of AAV particles from a mammalian host cell culture to form a drug product comprising the steps of (a) an acidification and clarification step; (b) a cation exchange chromatography step (Kaspar embodiment 9 on page 147). Kaspar teaches the process for cation exchange chromatography to separate viral capsids from a mixture of host cell proteins, host cell DNA, and host cell lipids (lines 30-31 on page 47). Kaspar teaches that the column is loaded with the sample, the column is washed with a loading buffer, and then an elution buffer is used to elute the sample of interest of the column (lines 3-4 on page 48). AAV is a non-enveloped virus as evidenced by addGene (paragraph 1 on page 1).
Kaspar teaches harvesting expanded viral particles and then adding an endonuclease to degrade both DNA and RNA, such as an endonuclease produced and purified from E. coli (lines 6-16on page 43).
Kaspar does not teach washing the cation exchange column with about 0.1 to about 2% Laureth-9.
Kondratova teaches that endotoxins are lipopolysaccharides (LPS) often detected in rAAV preparations (Abstract). Kondratova teaches subjecting endotoxin-contaminated rAAV to mild detergent treatment in order to break down LPS micelles (Abstract, and page 112, right column, paragraphs 1-2). Kondratova teaches that in most cases, recombinant AAV is prepared after transfection of HEK293 cells with plasmid DNA isolated from E. coli, which can lead to potential contamination with LPS from the E. coli (paragraph bridging pages 112-113).
Adie teaches a method of purifying a nucleic acid in a biological sample (“mixture”) comprising incubating the biological sample in the presence of 0.5 to 5% V/V polidocanol (Abstract and Adie claim 16). Adie teaches other names for the compound termed “polidocanol” including laureth-9 ([0033]). The nucleic acid binds to a binding material during the incubation and is optionally washed (Adie claim 18). Adie teaches a washing solution with an acidic pH ([0053]) and Adie teaches that the pH of the composition comprising polidocanol is acidic ([0048]). Adie teaches purifying the nucleic acid derived from a hepatitis A virus (Adie claim 23), which is a non-enveloped virus as evidenced by CDC (“Infectious Agent,” last line on page 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to replace Kaspar’s generic loading buffer used for washing the chromatography support with Adie’s 0.5 to 5% V/V polidocanol, which is a nonionic (mild) surfactant. The person of ordinary skill in the art would have been motivated to further purify the AAV by removing contaminants such as residual LPS introduced during processing (such as by the E. coli-derived endonuclease treatment after harvesting). The person of ordinary skill in the art would have had a reasonable expectation of success applying Adie’s 0.5 to 5% V/V polidocanol as a wash solution.
Regarding claims 81-82, Kaspar teaches culturing cells that have been transfected with a recombinant AAV virion, harvesting the expanded viral particles from the cells after a culture period, and purifying the viral particles via filtration to remove any intact cells or cellular debris (Kaspar embodiment 4 on page 147). Kaspar teaches filtering the harvested supernatant (a product of the culturing and harvesting steps) via depth filtration (Kaspar line 11 on page 10).
Regarding claim 71-72, Kaspar teaches harvesting the transfected cells by adding a lysis buffer to prepare a mixed bulk harvest (lines 21-22 and 31 on page 82), which is equivalent to a “paste” (mixture of solid cells and liquid). Kaspar also teaches an additional step of depth filtration to purify the viral particles (page 82, line 31 and line 14 on page 44). The viral particles are rAAV (see Kaspar claim 154).
Kaspar does not teach contacting the mixed bulk harvest (“paste”) with a solution comprising from about 0.1 % to about 2% Laureth-9 for about 1 minute to about 120 minutes.
Kondratova teaches that endotoxins are lipopolysaccharides (LPS) often detected in rAAV preparations (Abstract). Kondratova teaches subjecting endotoxin-contaminated rAAV to mild detergent treatment in order to break down LPS micelles (Abstract, and page 112, right column, paragraphs 1). Kondratova teaches that in most cases, recombinant AAV is prepared after transfection of HEK293 cells with plasmid DNA isolated from E. coli, which can lead to potential contamination with LPS from the E. coli (paragraph bridging pages 112-113).
Adie teaches a method of purifying a nucleic acid in a biological sample (“mixture’) comprising incubating the biological sample in the presence of 0.5 to 5% V/V polidocanol (Abstract and Adie claim 16). Adie teaches other names for the compound termed “polidocanol” including laureth-9 ([0033]). Adie teaches an incubation time between 10 seconds and 30 minutes (page 5, [0070]), which overlaps with the claimed range of about 1 minute to about 120 minutes.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further purify the rAAV of Kaspar by contacting the mixed bulk harvest or paste (comprising the genomic copies of rAAV and residual host cell proteins) with Adie’s 0.5 to 5% V/V polidocanol. The person of ordinary skill in the art would have been motivated to remove any endotoxins with the polidocanol (a surfactant). The person of ordinary skill in the art would have had a reasonable expectation of success given that Kondratova teaches mild detergents break down LPS.
Regarding claims 69 and 73, Kaspar teaches that the method results in a yield of more than 5 × 1015 vg per manufacturing batch (lines 20-21 on page 7). Kaspar does not teach the genomic titer of rAAV after filtration is greater than about 10 log10 vg/ml.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the concentration of the purified rAAV of Kaspar modified by Kondratova and Adie. The person of ordinary skill in the art would have had a reasonable expectation of success because concentration is a results-effective variable: diluting the rAAV in a greater liquid volume results in a lower concentration, whereas diluting the rAAV with less liquid volume results in a higher concentration.
Regarding claims 70 and 74-75, Kaspar teaches infectious titer by TCID50 (line 32 on page 103). The titer is on the order of 1010/mL (bottom line on page 103), which overlaps with the claims range of greater than 8log10TCID/mL. Kaspar suggests that the process may be advantageous for large-scale manufacture of rAAV (lines 1-2 on page 104). Kaspar achieves these results using a purification process comprising a step of acidification and clarification with a detergent (embodiments 9-10 on page 147). The detergent is an acidic detergent (lines 2-3 on page 47). Therefore, the person of ordinary skill in the art would have had a reasonable expectation of success in achieving similar results in the method of Kaspar modified by Kondratova and Adie because Adie’s Luareth-9 solution is acidic and comprises a surfactant ([0033] and [0048]).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CANDICE LEE SWIFT whose telephone number is (571)272-0177. The examiner can normally be reached M-F 8:00 AM-4:30 PM (Eastern).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise Humphrey can be reached at (571)272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657