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 .
Priority
This is a National Stage Entry under 35 U.S.C. 371 of International Patent Application No.
PCT/IB2021/060095, filed November 01, 2021, which claims priority to US Application Nos. 63/109049, filed November 03, 2020, 63/217194, filed June 30, 2021, and 63/253215, filed October 07, 2021.
Specification
The use of the term “Triton X-100" and "Brij-35", 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.
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.
Claim Rejections - 35 USC § 112
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.
Claim 75 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 75 recites, inter alia, “RHM4-1 (SEQ ID NO:5 of WO 2015/013313).” The sequence has not been provided in the Sequence Listing. See MPEP 2422.01(III). Moreover, MPEP 608.01(p) provides, in part:
(d) "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference.
SEQ ID NO: 5 of WO 2015/013313 is “essential material” at least because the sequence is explicitly recited in claim 75. As such, reference to the sequence in WO 2015/013313 constitutes an improper incorporation by reference, which does not satisfy the written description requirement.
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.
Claims 62 and 75 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 62 contains the trademark/trade name TritonTM X-100 and BrijTM-35. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe polyoxyethylene octyl phenyl ether and polyoxyethylene laural ether respectively and, accordingly, the identification/description is indefinite.
Claim 75 recites, inter alia, “RHM4-1 (SEQ ID NO:5 of WO 2015/013313).” It is unclear how the subject matter with the paratheses is intended to limit “RHM4-1.” For example, it is unclear if RHM4-1 is limited to SEQ ID NO: 5, or if SEQ ID NO: 5 represents a species of RHM4-1.
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.
Claims 56, 58 - 69, 71 - 72, and 75 are rejected under 35 U.S.C. 103 as being unpatentable over Hanak et al. (WO2020061581A1, hereinafter “Hanak”) in view of Chang et al. (US20200222524A1, hereinafter “Chang”) and Fielder et al. (US20200332266A1, hereinafter “Fielder”).
Regarding claim 56, Hanak teaches method of purifying a recombinant adeno-associated viral (rAAV) vector by anion exchange chromatography (AEX) (Page 3, Para 05) by diluting a solution comprising a rAAV vector to be purified with a dilution solution comprising a buffering agent and a detergent (Page 473, Fig. 214), then loading the diluted solution onto an AEX stationary phase under conditions sufficient for rAAV vector in said diluted solution to bind to said AEX stationary phase (Page 473, Fig. 214), and then eluting the rAAV vector from said AEX stationary phase with an elution solution that increases in conductivity as elution proceeds (Page 473, Fig. 214; see also Fig. 21, reproduced below).
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Regarding claim 58, Hanak teaches a solution comprising a rAAV vector to be purified is diluted 15-fold (Page 502, Fig. 225).
Regarding claim 59, Hanak teaches a dilution solution that has a pH of 9.05, and comprises 50mM of Tris and 0.05% of poloxamer 188 (Page 502, Fig. 225).
Regarding claim 60, Hanak teaches Tris as an acceptable buffering agent (Page 502, Fig. 225).
Regarding claim 62, Hanak teaches poloxamer 188 as an acceptable detergent (Page 502, Fig. 225).
Regarding claim 63, Hanak teaches that after diluting the solution, the pH is higher and the conductivity is lower of the diluted solution as the starting solution has a pH of 3.6 and a high conductivity (Page 472, Fig. 213) and a higher pH of 9.05 and lower conductivity (Page 473, Fig. 214) after dilution.
Regarding claim 64, Hanak teaches a pH of 9.05 after dilution (Page 472, Fig. 213).
Regarding claim 65, Hanak teaches a starting conductivity from approximately 0 mS/cm to 4 mS/cm (Page 507, Fig. 227C).
Regarding claim 66 and 67, Hanak teaches sodium chloride as an acceptable salt (Page 374, Fig. 122) for an elution solution.
Regarding claim 68, Hanak teaches an elution solution comprising of of 0 mM sodium chloride concentration at the beginning of elution and ends with a concentration of 1M sodium chloride (Page 502, Fig. 225).
Regarding claim 69, Hanak teaches a starting conductivity of about 0 mS/cm to a final conductivity of about 54 mS/cm (Page 507, Fig. 227C, reproduced below). The references do not teach the starting range of between 1.0 mS/cm and 2.5 mS/cm or an end range of 20 mS/cm to 35mS/cm. However, it would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal conductivity for use in the method taught by Hanak, Fielder, and Chang to maximize the elution of empty and full capsids at separate timepoints with a reasonable expectation of success. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such differences are 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Here, the instant claims encompass routing conductivity ranges for chromatography which evidences that a particular conductivity is not critical and readily obtained by routine optimization.
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Regarding claim 71, Hanak teaches measuring the UV light absorbance of the eluate at 260 nm and 280 nm and collecting a fraction of the eluate when the A260/A280 ratio is at least 1.24 (Page 174, Para 0959; Page 338, Fig. 133). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Regarding claim 72, Hanak teaches the proportions of full capsids eluted to be at least 77% (Page 571, Fig. 254).
Regarding claim 75, Hanak teaches the purification of AAV8 viruses (Page 3, Para 05).
Regarding claims 56, 59, and 61, the reference fails to teach the use of an amino acid in the dilution solution. However, the use of amino acids with histidine in particular was widely used to stabilize viruses, including AAVs. Chang describes the use and motivation to use histidine among other amino acids to stabilize AAVs in solution, i.e., “the amino acids in a virus formulation may preserve the integrity of capsid or envelope structures by protecting the virus from undesirable interactions with other molecules or surfaces (Page 8, Para 101; Page 2, Para 0029; Page 9 Para 0120). Furthermore, Fielder teaches the use of histidine from 50mM to 200mM to purify AAVs as a component of the dilution solution, wash buffer, and elution buffer (Page 12, Para 0152-154) demonstrating its use without interference of chromatographic purification processes, especially in instances where charge plays a role. Fielder also shows an increase in AAV capture by first using AEX followed by affinity chromatography (Page 25, Table 9, Table 10). Taken together, one of ordinary skill in the art would understand histidine to be beneficial in any step where viral integrity is important when electrostatic charge interactions are of concern. As such, the instant claim does not demonstrate any unexpected results.
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to add the histidine taught by Chang and Fielder to the dilution solution taught by Hanak in order to advantageously stabilize the AAVs as taught by Chang. One of ordinary skill in the art would have reasonable expectation of success in further selecting for full viral vectors given that these methods are well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim 57 is rejected under 35 U.S.C. 103 as being unpatentable over Hanak, Fielder, and Chang as applied to claims 56, 58 - 69, 71 - 72, and 75 above, and further in view of Nass et al. (Molecular Therapy, 2018, hereinafter "Nass").
As discussed above, claims 56, 58 - 69, 71 - 72, and 75 were rendered prima facie obvious by the teachings of Hanak, Fielder, and Chang.
The references fail to teach an affinity eluate as the solution comprising of a rAAV vector to be purified.
However, Nass teaches a combination affinity and anion exchange chromatography for, first, the removal of impurities, followed by the removal of empty cpasids (Page 44, Section: Materials and Methods, Chromatography; Page 33, Section: Introduction, Para 2 - 4).
Nass is considered analogous to the claimed invention because it is in the same field of purifying AAV and rAAV. Nass teaches the use of affinity chromatography to first remove impurities and isolate AAV capsids followed by AEX step to further remove empty capsids from the affinity elute Page 33, Section: Introduction, Para 2 – 4). While Hanak does not explicitly mention the use of an affinity elute for AEX, Hanak does mention the use of cation exchange chromatography elute for use in AEX purification, teaching the idea of multiple steps to remove impurities and improve the ratio of full to empty capsids Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to obtain a high purity of full viral particles as taught by Hanak using method taught by Nass because doing so would advantageously result in a starting solution enriched in AAV and lacking impurities for AEX. One of ordinary skill in the art would have reasonable expectation of success selecting for full viral vectors given that these methods are well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 70 are rejected under 35 U.S.C. 103 as being unpatentable over Hanak, Fielder, and Chang as applied to claims 56, 58 - 69, 71 - 72, and 75 above.
As discussed above, claims 56, 58 - 69, 71 - 72, and 75 were rendered prima facie obvious by the teachings of Hanak, Fielder, and Chang. As further discussed above, the references teach a dilution solution comprising Tris, histidine, and P188.
Regarding claim 70, Hanak teaches a dilution solution that has a pH of 9.05, and comprises 50mM of Tris, and 0.05% of poloxamer 188 (Page 502, Fig. 225) as well as the use of 50 mM sodium acetate to elute AAV during cation exchange chromatography. Furthermore, Qu et al. (J Virological Methods, 2007, hereinafter, “Qu”) teaches the use of 50 mM sodium acetate to elute full AAV using AEX (Page 3205, Col 2, Para 1). Fielder teaches the use of histidine in the dilution solution.
The references do not teach the concentrations of Tris, histidine, or P188, as claimed. However, it would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal amount of Tris, histidine, and P188 for use in the method taught by Hanak, Fielder, and Chang to maximize viral stability and recovery with a reasonable expectation of success. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Here, the instant claims encompass broad concentration ranges or, in some instances, no particular concentrations, which evidences that a particular concentration is not critical and readily obtained by routine optimization.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 73 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Hanak, Fielder, and Chang as applied to claims 56, 58 - 69, 71 - 72, and 75 above, and further in view of Zhang et al. (WO2019241535, hereinafter "Zhang").
As discussed above, claims 56, 58 - 69, 71 - 72, and 75 were rendered prima facie obvious by the teachings of Hanak, Fielder, and Chang.
The references fail to teach the specific use of a polystyrenedivinylbenzene (PS-DVB) particle with covalently bound quaternized polyethyleneimine as the stationary phase.
However, regarding claim 73, Zhang teaches the use of PorosTM 50 HQ, which is a PSDVB based resin with covalently bound quaternized polyethyleneimine (Page 18, Para 0011) for AEX to purify AAV. Regarding claim 74, Hanak teaches the dilution of an AAV amount of 4.3 x 1013 to a volume of 2.7 x 1011 vg/mL (Page 425, Fig. 170A). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Zhang is considered analogous to the claimed invention because it is in the same field of purifying AAV and rAAV. While Hanak does not explicitly mention a PS-DVB based resin with covalently bound quaternized polyethyleneimine, they do mention the use of a QA column, which is commonly used for AAV AEX purification. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to utilize the art-recognized method to obtain a high purity of full viral particles as taught by Hanak using the columns taught by Zhang because doing so would advantageously result in a streamlined process during AEX. One of ordinary skill in the art would have reasonable expectation of success selecting for full viral vectors given that these methods are well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Conclusion
NO CLAIM ARE ALLOWED
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANYAL H ALAM whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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/DANYAL HASSAN ALAM/ Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672