DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/16/2025 has been entered.
Applicant’s amendment, filed 09/16/2025, has been entered.
Claims 1-18 have been canceled.
Claims 19-41 are pending and currently under examination.
Claim Rejections - 35 USC § 103
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.
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.
Claim 19-41 are rejected under 35 U.S.C. 103 as being unpatentable over Grillo-Lopez et al. (US 2010/0003252 A1, cited in IDS) in view of Mingozzi et al. (Molecular Therapy vol. 20 no. 7, 1410-1416 July 2012, cited in IDS).
Grillo-Lopez et al. teach administration of viral vectors to a human followed by treatment with anti-CD20 antibody such as rituximab followed by readministration of the same viral vector (see Example 2, [0024]). The antibody can be administered as four weekly administrations (aka for a month, see [0176]). The anti CD20 antibody can be administered prior to the first administered dose of viral vector (see [0155]). The anti-CD20 antibody can be administered with rapamycin (an immunosuppressive agent) (see [0176], [0056],[0163]). Grillo-Lopez et al. do not teach the viral vector is rAAV. Mingozzi et al. teach that rituximab can be used to reduce immune responses against rAAV viral vectors encoding a transgene including when rAAV is readministered (see abstract, page 422, first column, first two paragraphs). It would have been prima facie obvious to one of ordinary skill in the art at the time of the earliest priority date of the instant application to have created the claimed invention because Grillo-Lopez et al. teach administration of viral vectors to a human followed by treatment with anti-CD20 antibody such as rituximab and rapamycin followed by readministration of the same viral vector, that the antibody can be administered as four weekly administrations and that the anti CD20 antibody can be administered prior to the first administered dose of rAAV whilst Mingozzi et al. teach that rituximab can be used to reduce immune responses against rAAV viral vectors including when rAAV is readministered. A routineer would determine the need for readministration of the rAAV based on routine experimentation (aka if the first rAAV was functioning than a subsequent rAAV would not necessarily be needed until the function was comprised). For example, if the patient received rAAV and rituximab for the first rAAV administration, then a second readministration of rituximab/rAAV would not be required until a subsequent immune response was detected. Grillo-Lopez et al. teach that the second administration of rAAV and rituximab occurs after the detection of an immune response against the administered vector (see Example 2). Rapamycin is an FDA approved clinically used drug administered on a daily base. One of ordinary skill in the art would have been motivated to do the aforementioned because Grillo-Lopez et al. teach administration of viral vectors to a human followed by treatment with anti-CD20 antibody such as rituximab and rapamycin followed by readministration of the same viral vector, that the antibody can be administered as four weekly administrations and that the anti CD20 antibody can be administered prior to the first administered dose of rAAV whilst Mingozzi et al. teach that rituximab can be used to reduce immune responses against rAAV viral vectors including when rAAV is readministered.
With regards to the limitation of “whereby said human subject serum concentration of antibodies against AAV is reduced overtime”, it is noted that Grillo-Lopez expressly taught that “Administration of anti-CD20 antibody will reduce or eliminate an immune response in the patient (e.g., by reducing anti-adenovirus antibody production), and thereby facilitate successful gene therapy retreatments” (see Example 2 [0176]). Furthermore, Mingozzi also taught that in one of experimental animal that received rituximab benefit of reducing the anti-AAV antibody titer to levels that allowed for successful vector readministration was observed (see page 1411, first paragraph). Upon reading the combined teachings, one of ordinary skill in the art would have reasonable expectation that administering rituximab in conjunction with rapamycin as taught by Grillo-Lopez would result in reduction of serum concentration of antibodies against AAV over time. Moreover, the ordinary skilled artisan would also have been motivated to use the method taught by Grillo-Lopez (i.e., administering an anti-CD20 antibody and rapamycin) to apply to the method taught by Mingozzi (i.e., administering rituximab with rAAV) in order to reduce or eliminate immune response in the patient such as reducing anti-AAV antibody production. Moreover, Grillo-Lopez also taught the same dose of 375mg/m2 (see [0176]) for the antibody and Mingozzi taught AAV8 vector (see Results).
The difference between the claimed invention and the prior art is the doses of rapamycin. However, it is noted that determination of dosage is routinely determined by the ordinary artisan was known as result effective variables that depend on the conditions of the patients. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) (determination of suitable dosage amounts in diuretic compositions considered a matter of routine experimentation and therefore obvious). One of ordinary skill in the art would appreciate the amount or dosage of rapamycin in the therapy could be adjusted to achieve optimum therapeutic efficacy.
With regards to AVV serotype 9 (AVV9), it is noted that although Mingozzi taught AVV6
and AVV8, it would have been obvious to one of ordinary skill in the art to use AVV9 because
AVV9 was well known in the art before the effective filing date of the claimed invention. For
example, Wu taught that AVV serotypes including AAV7, AAV8 and AAV9 have been found in
human or nonhuman primate tissue and well characterized for use in vector production (see,
e.g., Vector Production and Purification pages 316-317). One of ordinary skill would have been
motivated to use AAV9 given that AAV9 appears to be a vector that can outperform other AAV
serotypes in most tissue (page 318, second paragraph, last sentence). Moreover, the ordinary
artisan would have reasonable expectation of success given that AAV9 vector has been well
characterized and available for vector production.
Therefore, the invention, as a whole, was prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Applicant’s argument
Applicant argues that the prior art does not teach or suggest administration of anti-CD20 antibody at least once prior to and at least once after administration of a first rAAV vector. In response, it is noted that Grillo-Lopez et al. teach administration of viral vectors to a human followed by treatment with anti-CD20 antibody such as rituximab and rapamycin followed by readministration of the same viral vector, that the antibody can be administered as four weekly administrations and that the anti CD20 antibody can be administered prior to the first administered dose of rAAV whilst Mingozzi et al. teach that rituximab can be used to reduce immune responses against rAAV viral vectors including when rAAV is readministered. A person of ordinary skill in the art would determine the need for readministration of the rAAV based on routine experimentation (aka if the first rAAV was functioning than a subsequent rAAV would not necessarily be needed until the function was comprised). For example, if the patient received rAAV and rituximab for the first rAAV administration, then a second readministration of rituximab/rAAV would not be required until a subsequent immune response was detected. Grillo-Lopez et al. teach that the second administration of rAAV and rituximab occurs after the detection of an immune response against the administered vector (see Example 2). Furthermore, Grillo-Lopez taught that the anti-CD20 antibody can be administered prior to the first administered dose of therapeutic agent, such as a gene therapy vector (paragraphs 0155 and 0176). Given that the Grillo-Lopez taught that the anti-CD20 antibody can be administered before or after (paragraph [0155]) and that Mingozzi taught that the anti-CD20 antibody can be administered simultaneously (page 1414, right column, 5 paragraph), one of ordinary skill in the art would have good reason to administer the CD20 antibody both before and after given the limited possibilities. Moreover, the frequency and timing of the administration are routinely determined by the ordinary artisan as result effective variables that could be adjusted to achieve optimum therapeutic efficacy.
Applicant further argues that Grillo-Lopez taught adenoviral vector which is different from and not substitutable with recombinant adeno-associated viral vector (rAAV) as recited in the present claims. Applicant relies on Zaiss and Chirmule to show the difference between Adenovirus and AAV and Sumner-Jones to show lack of predictability in using rAAV vector. Applicant alleges that in view of the teachings of Zaiss, Chirmule and Sumner-Jones, “the skilled artisan would not have reasonably predicted that application of Grillo-Lopez’s teachings to a human patient receiving repeated administrations of rAAV would successfully provide a reduction of anti-AAV antibodies” (page 11 of Remarks).
In response, it is first noted that although Grillo-Lopez disclosed adenoviral vector as one of the embodiments, the prior art did not in any way suggest it is the only viral vector as shown in below paragraph [0024].
By "gene therapy" is meant the general approach of introducing nucleic acid into a mammal to be treated therewith. The nucleic acid may encode a polypeptide of interest or may be antisense nucleic acid. One or more components of a gene therapy vector or composition may be immunogenic in a mammal treated therewith. For example, viral vectors (such as adenovirus, Herpes simplex I virus or retrovirus); lipids; and/or targeting molecules in the composition may induce an immune response in a mammal treated therewith.
With regard to Zaiss, it is noted that Zaiss actually supports substitution of functional equivalent of adenoviral vector with AAV vector in gene therapy. In fact, Zaiss even provides motivation to use a rAAV vector over an adenovirus vector when it disclosed that rAAV vectors activate the innate immune response to a lesser extent than do adenovirus vectors (see, e.g., Abstract). Given that both adenovirus vectors and AAV vectors were well-known vectors for gene therapy in the art before the effective filing date of the claimed invention, one of ordinary skill in the art would have been motivated to select AAV vectors for gene therapy because they elicit less undesired immune response which was the problem that Grillo-Lopez was trying to solve by using CD20 antibodies in conjunction with the viral vectors.
Sumner-Jones disclosed that antibody response to AAV hindered repeated administration of rAAV for therapeutic transgene expression in hosts. Sumner-Jones did not use anti-CD20 antibody for immunosuppression to combat the antibody response. Moreover, Sumner-Jones expressed desire for immunosuppressive strategies in order to allow repeated rAAV administration. In response to Applicant’s argument, it is first noted that Sumner-Jones is not commensurate in scope with the claimed invention in that it did not disclose use of anti-CD20 antibody. Moreover, contrary to Applicant’s argument, the teaching of Sumner-Jones provides evidence that one of ordinary skill in the art would seek out an immunosuppressive strategy to decrease the production of anti-AAV antibodies and Rituximab would be an obvious choice to try given its well-known function in B cell suppression. Reasonable expectation of success does not require absolute certainty or predictability of success. The problem Grillo-Lopez, Zais, and Sumner-Jones have in common is the undesired antibody production hindering repeat administration of transgene-expressing viral vectors. The problem to be solved motivates the ordinary skill in the art would to undertake further study. Motivation to undertake further study does not imply lack of predictability or awareness of the likely result; rather, studies are frequently conducted to confirm what is suspected to be true as a case in point as exemplified by Mingozzi.
Applicant further argues that Mingozzi teaches away from the claimed methods because Mingozzi reported a “50% failure rate” in providing reduction of anti-AAV antibody titer following treating with rituximab in conjunction with AAV gene transfer in nonhuman primates. In response, it is noted Applicant’s alleged “50% failure rate” is a mischaracterization of the teachings by Mingozzi. Mingozzi reported that the effect of immunosuppression with rituximab was observed in one of the two rhesus macaques treated and vector readministration in the absence of anti-vector antibodies resulted in increased transgene expression (see Results page 1412 and Figure 3). As such, Mingozzi has demonstrated that depletion of B cells with rituximab resulted in a drop in anti-AAV antibodies and in turn increased the transgene expression of the AAV vector. As noted above, reasonable expectation of success does not require absolute certainty or predictability of success. In view of the disclosure by Mingozzi, one of ordinary skill in the art would have been motivated to use rituximab in gene therapy with rAAV vector.
With regards to rapamycin in combination with anti-CD20 antibody, it is noted that Grillo-Lopez disclosed that immunosuppressive agents can be administered with anti-CD20 antibody and that rapamycin is one of the disclosed immunosuppressive agents. Therefore, it would have been obvious for one of ordinary skill in the art to use rapamycin in combination with anti-CD20 antibody. Applicant has not provided any evidence of criticality with regard to using rapamycin. Similarly, with regards to the dose of rapamycin, one of ordinary skill in the art would have good reason to determine the dosage in order to maintain an optimum therapeutic efficacy that is indicated by serum trough level as claimed.
Applicant further argues that there is no motivation to combine the two references to arrive at the claimed methods. In response, it is noted that the rational to combine prior art teaching does not have to be limited to Applicant's. Applicant is reminded that “obviousness can be established for achieving the claimed product for different reasons and the prior art/examiner does not need to know all of the properties of the claimed invention” In re Dillon, 16 USPQ2d 1897 (Fed. Cir. 1990); however there must be some suggestion or motivation. Therefore, the reason or motivation to combine may often suggest doing what the inventor has done, but for a different purpose or to solve a different problem than that asserted by the inventor. See MPEP 2144.
Here, Grillo-Lopez taught using anti-CD20 antibody such as rituximab to the purpose of blocking immune response foreign antigen such as viral vector. Mingozzi also taught rituximab can be used to reduce immune response against viral vectors such as rAAV. The rationale to support a conclusion that the claims would have been obvious is that all the claimed elements (e.g., rituximab can block immune response before and after administering a viral vector; rituximab can reduce immune responses against rAAV viral vectors including when rAAV is readministered) were known in the prior art and one skilled in the art could have arrived at the claimed invention by using known methods with no change in their respective function and the combination would have yielded nothing more than the predictable result of a using rituximab to block or reduce immune response before and after the administration of viral vector rAAV.
Applicant’s argument has been considered but has not been found convincing. Therefore, the rejection of record is maintained as it applies to amendment claims
Applicant further asserts surprising and unexpected success shown in Figures 2A and 2B. In response, it is noted that the two experiments compared subjects who was treated with rituximab to subjects who was not treated with rituximab. Given that rituximab was a known B cell deplete and that Grillo-Lopez expressly taught that “administration of anti-CD20 antibody will reduce or eliminate an immune response in the patient (e.g., by reducing anti-adenovirus antibody production), and thereby facilitate successful gene therapy retreatments” (paragraph 0176), one of ordinary skill in the art would have reasonable expectation to see a reduction in antibodies against AAV in patients treated with rituximab. Therefore, Applicant’s alleged surprising and unexpected success has not been found convincing.
Applicant’s argument has been considered in full but has not been found convincing. Therefore, the rejection is maintained.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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/SHARON X WEN/Primary Examiner, Art Unit 1641