Notice of Pre–AIA or AIA Status
1. 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
Status of Claims
2. Applicant’s preliminary amendment of the instant application, which was originally submitted on 05/17/2023 and later amended on 09/22/2023, is acknowledged by the Examiner. The claims filed on 09/22/2023 were examined. Claims 3, 5, 7, 10, 12, 13, 15, 16, 18, 20, 22, 23, 25, 28 – 33, 35, 36, 38, 40 – 47, and 50 – 62 are cancelled. Claims 1, 2, 4, 6, 8, 9, 11, 14, 17, 19, 21, 24, 26, 27, 34, 37, 39, 48, and 49 are pending and under review.
Priority
3. The instant application claims priority to U.S. Provisional Application No. 63/342,961 of filed on 05/17/2022. Priority is granted to the provisional application for claims 1, 2, 4, 6, 8, 9, 11, 14, 17, 19, 21, 24, 26, 27, 34, 37, 39, 48, and 49 of the instant application.
Information Disclosure Statement
4. No information disclosure statement (IDS) was present at the time of this office action. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO–892, they have not been considered. Applicant is reminded of the duty to disclose information to the Office which is material to patentability as defined in 37 CFR 1.56. This includes a list of all patents, publications, or other information that should be considered by the Office pursuant to 37 CFR 1.98(b). See MPEP § 609.
Specification
5. 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.
6. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser–executable code on page 7. Applicant is required to delete the embedded hyperlink and/or other form of browser–executable code; references to websites should be limited to the top–level domain name without any prefix such as http:// or other browser–executable code. See MPEP § 608.01.
7. The use of the terms POROS™ on pages 21, 26, 41, and 42; AKTA Avant™ on page 21; Cytiva™ on pages 21 and 41; Progen™ on pages 21, 41, and 45; Thermo Fisher Scientific™ on pages 21, 26, and 41, DynaPro™ on pages 21, 42, and 45; Repligen on page 41; J.T. Baker™ on page 41; SAFC™ on page 41; Pfanstiehl™ on page 41; BASF™ on page 41; VWR on page 41; Millipore Sigma on page 41; Omnifit® EZ columns on page 41; HiScale™ columns on page 41; Pellicon® on pages 41 and 44; KrosFlo® on pages 41 and 44; SpectraMax® on pages 41 and 45; ChemiDoc™ on page 42; ArcticZymes™ on page 42; Bio–Rad on page 42; UNICORN™ on page 43, and others in the specification, which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, ℠, or ® following the terms. 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. Applicant is required to properly annotate all trade names and/or marks that are present in the specification.
8. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Drawings
9. The instant application contains at least on drawing executed in color. FIGs. 2, 12A, and 12B have multiple lines that refer to and are differentiated by various colors. Applicant filed a petition on 05/17/2023 to accept color drawings for FIGs. 2, 12A, and 12B under 37 CFR 1.84(a)(2). The petition was granted on 10/20/2023. See below for reasoning:
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
10. Claims 4, 6, 9, 14, and 17 are objected to because of the following informalities:
In claim 4, line 2; claim 6, line 2; claim 9, line 16; claim 14, line 2; and claim 17, line 2; the acronym “mM” is defined as being “millimolar”. However, the acronym has previously been defined in claim 2, line 2. An acronym should only be defined the first time it appears in each independent claim or the first time it appears in the group of claims under each independent claim.
Appropriate correction is required.
Claim Rejections – 35 USC § 112
35 USC § 112(b)
11. 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.
12. Claims 1, 2, 4, 6, 8, 9, 11, 14, 17, 19, 21, 24, 26, 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.
13. Claims 1, 8, and 9 are unclear and vague, which renders the claims indefinite. The phrase “…wherein said one or more impurities comprise rAAV vector particle aggregates, rAAV vector particles that do not include said therapeutic nucleic acid molecule, and aggregates of rAAV vector particles and rAAV vector particles that do not include said therapeutic nucleic acid molecule” in lines 5 – 8 of the claims is unclear. How do these populations differ? What do they contain? Is it that the “rAAV vector particle aggregates” are aggregates of just rAAV on their own and the “aggregates of rAAV vector particles and rAAV vector particles that do not include said therapeutic nucleic acid molecule” are aggregates of both rAAV and empty particles? Or is it that “rAAV vector particle aggregates” and “aggregates of rAAV vector particles and rAAV vector particles that do not include said therapeutic nucleic acid molecule” are the same population? The claims are rendered indefinite due to this ambiguity in the language. Claims 2, 4, 6, 11, 14, 17, 19, 21, 24, 26, 27, 34, 37, 39, 48, and 49 are rejected by virtue of their dependency on claims 1, 8, and/or 9.
14. Claims 1, 8, and 9 are unclear and vague, which renders the claims indefinite. It is not clear if both of the first and second elution buffers are required to get the desired eluant, or just one of them, and if one, which one. The presence of multiple very different interpretations of the same claim language renders the claims indefinite. Claims 2, 4, 6, 11, 14, 17, 19, 21, 24, 26, 34, 37, 39, 48, and 49 are rejected under this indefiniteness issue by virtue of their dependency on claims 1, 8, or 9. Claim 27, which depends upon claim 1, provides some clarity in that the first elution buffer is decreased linearly while the second elution buffer is increased. However, the other claims are still rendered indefinite as they do not depend on claim 27.
15. The term “about” in claims 2, 4, 6, 9, 11, 14, 17, and 26 is a relative term and subjective, which renders the claims 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. How close one value needs to be “about” another is not defined in the claims or the specification. Thus, the claims that recite “about” are rendered indefinite. It is suggested that every iteration of the term be removed in its current usage.
16. Claim 27 recites the limitation "an eluant" in 2 of the claim. There is insufficient antecedent basis for this limitation in the claim. The eluant is acquired from claim 1(c). This raises the question of where is the eluant coming from? Is it that the eluant has been obtained from a first column and is being applied to a second column? Or is it that the eluant being applied to the column is the filtered and clarified lysate mentioned in claim 39? The claim lacks sufficient antecedent basis and is thus rendered indefinite.
Claim Rejections – 35 USC § 103
17. 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.
18. Claims 1, 2, 4, 6, 8, 9, 11, 14, 17, 19, 21, 24, 26, 27, 34, 37, 39, 48, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Lock, M., and Alvira, M. (US 2021/0348132 A1; Published 11/11/2021), hereby Lock, in further view of Tomkowicz, B. E., et. al. (US 2022/0040305 A1; Published 02/10/2022), hereby Tomkowicz; and Joshi, P. R. H., et. al., (2021), Development of a scalable and robust AEX method for enriched rAAV preparations in genome–containing VCs of serotypes 5, 6, 8, and 9. Molecular Therapy: Methods & Clinical Development, 21, 341 – 356 (Published June 2021), hereby Joshi; as supported by Dickerson, R., et. al. (2021). Separating Empty and Full Recombinant Adeno–Associated Virus Particles Using Isocratic Anion Exchange Chromatography. Biotechnology Journal, 16(1), e2000015 (Published 01/08/2021), hereby Dickerson.
Lock teaches a scalable method for separating genome–containing recombinant adeno–associated virus (rAAV) vector particles from genome–deficient rAAV intermediates, i.e., a method to separate full, pharmacologically active particles from empty capsids (abstract; page 1, paragraph 0009; page 2, paragraph 0014), as defined in instant claims 1, 8, 9, and 39. It is further taught that rAAV vector particles may be harvested from rAAV production cultures by lysing the host cells of the production culture (page 8, paragraph 0060; page 9, paragraph 0073), as required in instant claim 39. Lock goes on to teach that rAAV production cultures are a mixture that is contaminated with host cell proteins, host cell DNA, plasmid DNA, helper virus, helper virus proteins, helper virus DNA, plasmids, cellular proteins, media components, unassembled rAAV, and rAAV intermediates (page 3, paragraphs 0021 – 0024; page 14, claim 5), as recited in instant claims 1, 8, 9, and 39. Page 9, paragraph 0075 continues to teach that the rAAV production culture harvest is clarified by filtration to remove host cell debris, as disclosed in instant claim 39. It is further taught that the lysed and clarified solution is then subjected to anion exchange chromatography (AEX) to separate the full, or DNA–carrying, viral particles from the contaminating, empty particles (example 1, page 11, paragraphs 0108 – 0130), as required in instant claims 1, 8, 9, and 39. Lock teaches that this solution may be in 100% of a first elution buffer, i.e., Buffer A, that allows binding to the AEX column, wherein the column is comprised of a strong anion exchange resin that may be a quaternary amine ion exchange resin (page 4, paragraph 0034; page 5, paragraph 0034; page 15, claims 8 and 14), as stated in instant claims 1, 8, 9, 27, 34, and 37. It is further taught that during AEX, the proportion of Buffer A is decreased from 100% to 0% while the proportion of a second elution buffer, i.e., Buffer B, is increased from 0% to 100%, resulting in a linear salt gradient (page 4, paragraph 0032; page 5, paragraph 0040; page 11, paragraph 0127), as defined in instant claim 27. Lock goes on to teach that fractions are collected from the column as the concentration of Buffer B is increased, wherein the rAAV particles are eluted from the column and purified of the contaminants (page 10, paragraphs 0084 and 0097; page 15, claim 22), as recited in instants claims 1, 8, and 9. It is further taught by Lock that Buffer A and Buffer B can both contain bis–tris propane (BTP; page 5, paragraph 0038), as stated in instant claim 19. Lock also teaches that both Buffer A and Buffer B are comprised of a salt, i.e., sodium chloride (NaCl), wherein the ionic strength of the salt is in the range of 10 mM to about 200 mM (page 5, paragraphs 0037, 0039, and 0042), as stated in instant claim 9. Lock teaches that both Buffer A and Buffer B are comprised of a salt equivalent, including sulfate (page 5, paragraphs 0037, 0039, and 0042), as required in instant claims 1, 2, 4, 6, 8, 11, 14, and 17.
While Lock does teach that the AEX method described above can be applied to rAAV serotype 1 (rAAV1) viral particles (page 1, paragraph 0009), as required in instant claim 48, it fails to teach that the purification method can be applied to other serotypes of rAAV, including AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, and AAV10, as disclosed in instant claims 48 and 49. However, Tomkowicz teaches a method to purify and formulate rAAV particles, wherein the rAAV particles can be AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, and AAV10 (page 1, paragraph 0002; page 2, paragraph 0022; page 3, paragraph 0043; page 6, paragraph 0070; page 10, paragraph 0131; page 37, claim 16), as defined in instant claim 48. It is further taught that the AAV comprises or consists essentially of AAV5 (page 10, paragraph 0131), as recited in instant claim 49. Tomkowicz also teaches that the buffer formulation comprises the rAAV and one or more buffering agent, a cryoprotectant, a non–ionic surfactant, and a pharmaceutically acceptable salt (abstract; page 1, paragraph 0005). It is taught that the cryoprotectant is a sugar, i.e., sucrose (page 1, paragraph 0008; page 3, paragraph 0040; page 5, paragraph 0058; page 12, paragraph 0140; page 37, claim 8), as disclosed in instant claim 24; the non–ionic surfactant can be a poloxamer, including poloxamer 188 (pages 1 and 2, paragraphs 0010 – 0018; page 3, paragraph 0041; pages 5 and 6, paragraphs 0059 – 0067; pages 16 and 17, paragraphs 0166 – 0172; page 37, claim 11), as defined in the instant specification and claim 21; and the pharmaceutically acceptable salt is selected from a group that includes a magnesium salt, a sulfate salt, and a chloride salt (page 1, paragraph 0007; page 3, paragraph 0038; page 5, paragraph 0056; page 9, paragraph 0113), as stated in instant claims 1, 8, and 9. Tomkowicz continues to teach that the salt concentration is about 1 mM to 49 mM (page 14, paragraph 0149; page 38, claim 27), as recited in instant claims 2, 4, 6, 11, 14, and 17. It is further taught that the pH of the system is about 9.0 (page 2, paragraph 0020; page 3, paragraph 0042; page 6, paragraph 0069; page 11, paragraph 0137; page 14, paragraph 0151), as required in instant claim 26.
Lock and Tomkowicz are considered to be analogous to the claimed invention because both are methods for the purification/separation of rAAV viral particles from impurities using AEX. Based on prior art teachings, it would have been obvious to a person having ordinary skill in the art to lyse and clarify the host cells, then apply the clarified lysate to the AEX column with the bis–tris propane and linear salt gradient of Lock using the buffer conditions set forth by Tomkowicz, including the usage of poloxamer, sucrose, and a pharmaceutically acceptable salt at a pH of 9.0. This obviousness is mainly owed to both references teaching purification of the same subtype of rAAV particles. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Lock and Tomkowicz before the effective filing date of the claimed invention with a reasonable expectation of success to address the unmet need of a formulation containing highly pure AAV particles with improved stability and minimal aggregation (Tomkowicz; page 1, paragraph 0004). All the claimed elements were known in the prior art. It would have been obvious to a person having ordinary skill in the art to have combined the elements as claimed by known methods with no change in their respective functions. The combination would have yielded nothing more than predictable results to one having ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143A and 2143.02.
While Lock does teach that the salt in the buffer can be a single salt, a mixture of NaCl with other salts, or a mixture of salts which do not include NaCl, but are compatible with AEX (page 5, paragraph 0037), neither Lock and Tomkowicz teach the explicit usage of magnesium sulfate (MgSO4) as the sulfate salt, i.e., the first salt, in the first elution buffer, as stated in instant claims 1, 2, 8, 9, and 11; or the usage of MgSO4 and magnesium chloride (MgCl2) as the sulfate salt and chloride salt, i.e., the second and third salt, respectively, in the second buffer, as required in instant claims 1, 4, 6, 8, 9, 14, and 17. However, Joshi teaches that there is a 3–fold difference in ionic strength between chloride and sulfate salts, wherein rAAV5 elutes at a lower salt concentration of sulfate over chloride during AEX (page 342, righthand column). It is further taught that other rAAVs, including rAAV6 and rAAV8, elute best in MgSO4, wherein the addition of extra MgSO4, i.e., salt supplementation, helps retain components in the flowthrough, which may otherwise bind in the absence of additional salt and elute at low salt concentrations (page 346, lefthand column; see also Figure S3C as reproduced below). In support of this, Dickerson teaches that the combination of MgCl2 and NaCl in the elution buffer improved the separation between empty and full rAAV2 during AEX (page 3, section 2.2). Moreover, both Joshi and Dickerson teach that the target elution buffer having a pH of 9 provides for optimal separation of the full rAAVs from the empty rAAVs. Therefore, “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). In light of this case law, it would have been obvious to a person having ordinary skill in the art to have combined MgSO4 with MgCl2 to increase the ionic strength of the second buffer, wherein the dual gradient results in an elution
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pool enriched in full rAAV particles (Dickerson; page 1, abstract, page 3, section 2.2).
Lock, Tomkowicz, Joshi, and Dickerson are considered to be analogous to the claimed invention because all are methods for the separation of rAAV viral particles from impurities using AEX. Based on prior art teachings, it would have been obvious to a person having ordinary skill in the art to apply the clarified lysate to the AEX column of Lock using the buffer conditions set forth by Tomkowicz, as discussed above on pages 11 and 12, wherein the first elution buffer has MgSO4 and the second elution buffer has MgSO4 and MgCl2 as disclosed by Joshi and supported by Dickerson. This obviousness is mainly owed to all references teaching purification of the various subtypes of rAAV particles, including rAAV1, rAAV2, rAAV5, rAAV6, and rAAV8. Therefore, it would have been obvious to a person having ordinary skill in the art to have combined the teachings of Lock, Tomkowicz, Joshi, and Dickerson before the effective filing date of the claimed invention with a reasonable expectation of success to ensure high therapeutic potency of rAAV products and improve their clinical safety profile by consistently producing the product with low levels of empty capsids (Dickerson; page 1, introduction, righthand column). All the claimed elements were known in the prior art. It would have been obvious for a person having ordinary skill in the art to have applied a known technique to a known method ready for improvement to yield predictable results and an improved system. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415–421, 82 USPQ2d 1385, 1395–97 (2007) and MPEP §§ 2143d and 2143.02.
Lock, Tomkowicz, Joshi, and Dickerson do not teach the exact concentration of the MgSO4 and/or MgCl2 in the first and/or second elution buffer, as disclosed in instant claims 2, 4, 6, 11, 14, and 17. However, the buffer conditions, including the salt concentration is clearly a result effective parameter that a person having ordinary skill in the art would routinely optimize. This is because the buffer conditions, i.e., the salt concentration, will determine the state of all components in the solution and on the column, including whether the proteins are aggregated, folded, and/or unfolded, as well as when each component of the solution will elute from the column. Thus, the concentrations of all salts in the claims are result effective parameters that would have been found by routine experimentation before filing of the instant application. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient, i.e., the buffer, needed to achieve the desired results. The principle of law states from MPEP §§ 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). In light of this case law, Lock teaches that both Buffer A and Buffer B are comprised of a salt equivalent, including sulfate, that has an ionic strength in the range of 10 mM to about 200 mM (page 5, paragraphs 0037, 0039, and 0042), as required in instant claims 1, 2, 4, 6, 8, 11, 14, and 17. Tomkowicz also teaches that the salt concentration is about 1 mM to about 200 mM (page 14, paragraph 0149; page 38, claim 27), as stated in instant claims 1, 2, 4, 6, 8, 11, 14, and 17.
Conclusion
19. Claims 1, 2, 4, 6, 8, 9, 11, 14, 17, 19, 21, 24, 26, 27, 34, 37, 39, 48, and 49 are rejected. No claims are allowed.
20. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Lock, M. and Alvira, M. (US 2021/0277364 A1; Published 09/09/2021) teaches the same purification scheme as taught by Lock in paragraph 12, but for rAAV8 instead of rAAV1, which is claimed in instant claim 48.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Hallie N. Pennington, Ph.D. whose telephone number is (571)272–6781. The examiner can normally be reached M–Th 7:30–5:30 ET.
Examiner interviews are available via telephone, in–person, and video conferencing using a USPTO supplied web–based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at (571)270–3497. The fax phone number for the organization where this application or proceeding is assigned is 571–273–8300.
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/HALLIE N. PENNINGTON, PH.D./Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671