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 .
Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/8/2026 has been entered.
Claims 1-4, 8-11, 13, 17-19, 23, 26, and 28-30 are pending. Claims 17-19 and 28-30 are withdrawn from consideration, as being directed to a non-elected invention. Claims 1-4, 8-11, 13, 23, and 26 have been considered on the merits.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claim 13 under 35 U.S.C 112(b)
Amendments to the claims overcome the rejection of record. The rejection is withdrawn.
RE: Rejection of claim 13 under 35 U.S.C 112(d)
Applicant’s amended claim 13 to require an increased expression of a disease gene. This amendment does not further limit the scope of claim 10. Given that GAA is a disease gene, expression of GAA using a recombinant viral vector would necessarily increase expression of GAA (See rejection below). The rejection is maintained.
RE: Rejection of claims 1-4, 8-11, 13, 23 and 26 under 35 U.S.C. 103 over Ronzitti et al (Ann Transl Med. 2019) in view of Blumenkranz and Gasmi (WO2017218981A2) and Szalay (US20140271549A1)
Applicants traverse the rejection of record on the grounds that the cited references do not teach reducing toxicity associated with recombinant viral vector therapy by administering an antibiotic. Instead, the antibiotic of Szalay is directed to improving efficacy of viral therapy by using an antibiotic to reduce commensal bacteria. Additionally, applicants argue there is no reasonable expectation of success because none of the cited references connect antibiotic administration to reduction of AAV-induced toxicity.
In response, the argument have been fully considered but are not found convincing. Applicants arguments are drawn to a mechanism of action that does not affect the active steps of the method. Instead, the mechanism of action is an inherent effect of co-administering an antibiotic with a viral vector. Additionally, while Szalay teaches a different beneficial effect of administering an antibiotic with a viral therapy than the instant application, it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant (See MPEP2144(V) and In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006)).
Applicants further argue the mechanisms inducing toxicity in Ronzitti et al differ from those of Szalay and thus the conclusion that modulating the commensal bacteria would reduce immune-mediated toxicity associated with AAV gene therapy is based on impermissible hindsight reconstruction.
In response, this argument is found convincing. Szalay teaches coadministration of a viral vector therapy and a compound that can decrease toxicity of the virus. The compound can comprise an anti-cancer antibiotic (See ¶0426-0427). However, macrolides and tetracycline antibiotics are not listed among the anti-cancer antibiotics. Instead, Szalay teaches macrolides and tetracycline antibiotics can be used to increase efficacy of the viral vector therapy. The rejection has been modified.
Applicants further argue the cited references are directed to different diseases and are thus not directed to the same problem or field of endeavor.
In response, the argument has been fully considered but is not found convincing. While the cited references exemplify treatment of different diseases, the cited references all teach methods of gene therapy using a viral vector.
Applicants further argue Szalay lists tetracycline or macrolide antibiotics among many possible options but does not identify these classes as preferred.
In response, the argument has been fully considered but is not found convincing. Szalay teaches tetracycline and macrolide antibiotics can be used in the method.
The rejection has been modified.
New/Maintained Rejections
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 13 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 13 requires GAA to increase expression of a disease gene. Ronzitti teaches Pompe disease is caused by mutation in the acid alpha glucosidase (GAA) gene which lead to loss of GAA expression (See abstract). Therefore, GAA is a disease gene. Expressing a heterologous copy of GAA using a recombinant viral vector would therefore necessarily increase expression of the disease gene (GAA). Thus, claim 13 does not limit the scope of claim 10.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
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 1-4, 8-11, 13, 23 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Ronzitti et al (Ann Transl Med. 2019) in view of Blumenkranz and Gasmi (WO2017218981A2) and Szalay (US20140271549A1).
Ronzitti et al reviews the use of gene therapy (reads on treatment using a recombinant viral vector) in treatment of Pompe disease (reads on glycogen storage type II disease) (See abstract). Ronzitti teaches Pompe disease is caused by mutation in the acid alpha glucosidase (GAA) gene which lead to loss of GAA expression (See abstract). Over the past two decades, various AAV vectors encoding GAA to rescue Pompe disease models have been tested (See Sec. Intramuscular and systemic gene transfer). Gene therapy provides a solution for expressing GAA long term thereby improving treatment methods (See abstract). Additionally, Ronzitti teaches gene therapy treatments for Pompe disease have been tested in preclinical animal models and early phase clinical trials (See sections Liver gene therapy for PD and Other gene therapy approaches to PD). Ronzitti et al further teaches a challenge to systemic delivery of an AAV is the requirement for high doses of vector (exceeding 1,014 vector genome/kg) which increases the risk of anti-GAA antibody formation and potential immunotoxicities (See Sec. Intramuscular and systemic gene transfer).
Regarding claims 1 and 2: Ronzitti et al teaches a method of treating Pompe disease comprising administering an AAV (reads on a recombinant viral vector) encoding GAA (reads on a heterologous nucleic acid sequence encoding GAA). Additionally, Ronzitti et al teaches systemic administration of AAVs is a challenge because it requires administration of high doses of vector which increase the risk of immunotoxicity.
Ronzitti et al does not disclose a method of reducing toxicity by co-administering the AAV and an antibiotic of the tetracycline or macrolides families of antibiotics.
Blumenkranz and Gasmi disclose a method of treating a subject with ocular neovascularization, using a composition comprising rAAV vector (see abstract). The method can further comprise administering an antibiotic (See claim 24 and ¶0007), and in some instances, a corticosteroid, such as prednisone (See ¶0139). The antibiotic is administered following administration of the rAAV composition (see ¶0007).
Szalay discloses a method of enhancing the effectiveness of a therapeutic virus comprising administering an antibiotic with, before, after or during treatment with a therapeutic virus (See claim 1). The therapeutic virus can be a retrovirus, adenovirus, lentivirus, herpes simplex virus, poxvirus, or adeno-associated virus (See claim 4) and can be modulated to reduce toxicity (¶0301) Exemplary antibiotics of the method include tetracyclines and macrolides (See ¶0015).
Given that Ronzitti et al teaches methods of treating Pompe disease with an AAV expressing GAA, Blumenkranz and Gasmi and Szalay teach methods comprising administering a therapeutic virus such as an AAV, along with an antibiotic, and Szalay further teaches co-administration of an antibiotic with a viral vector therapy improves efficacy of the viral vector therapy, it would have been prima facie obvious to add an antibiotic to the treatment method of Ronzitti et al in order to improve efficacy of the viral vector.
Additionally, Szalay teaches tetracycline or macrolides antibiotics are suitable antibiotics thus it would have been obvious to use a tetracycline or macrolides antibiotic as the antibiotic in the modified method. One would have been motivated to add an antibiotic such as a tetracycline or macrolides antibiotic to the method of Ronzitti et al in order to improve efficacy of the AAV. While Szalay does not recognize that administering an antibiotic reduces viral toxicity, this is an inherent effect of the antibiotic. There is a reasonable expectation of success because Blumenkranz and Gasmi and Szalay antibiotics can be co-administered with an AAV and Szalay further teaches tetracycline and macrolides antibiotics can improve efficacy of a viral vector therapy.
Regarding claims 3: Following the discussion of claim 1 above, Ronzitti et al teaches a method of treating Pompe disease by administering an AAV which encodes GAA.
Ronzitti et al is silent as to whether the treatment method further comprises prednisone.
Szalay et al teaches coadministration with prednisone and further teaches combination therapy with a therapeutic agent (e.g. prednisone) and a therapeutic virus can be effective in situations when a single agent treatment is not effective (See ¶431)
Given that Ronzitti et al teaches a method of treating a disease with an AAV and Szalay et al teaches a combination therapies of a therapeutic virus and a therapeutic agent such as prednisone can improve treatments in which single agent therapy was not effective, it would have been prima facie obvious at add prednisone to the treatment method of Ronzitti et al. One would have been motivated to add prednisone to the treatment method of Ronzitti et al in order to make a more robust treatment method. There is a reasonable expectation of success because Szalay teaches combination therapies can be more effective than single agent therapies.
Regarding claim 4: Following the discussion of claim 1 above, Ronzitti et al teaches a method of treating Pompe disease by administering an AAV which encodes GAA. Ronzitti et al does not disclose the method comprises administration of prednisone, thus the treatment method of Ronzitti et al does not comprise prednisone.
Regarding claim 8: Following the discussion of claim 1 above, the treatment method of Ronzitti et al comprises administration of an AAV.
Regarding claim 9: Following the discussion of claim 1 above, Ronzitti et al teaches a method of treating Pompe disease comprising administration of an AAV encoding GAA. Ronzitti et al further teaches treatment methods with systemic administration require high doses of vector but those high doses can cause immunotoxicity.
Ronzitti et al does not teach how much viral vector is administered.
Although Ronzitti et al does not teach the amount of viral vector administered, it would have been prima facie obvious to optimize the amount of viral vector to be administered, and arrive at the claimed amount of greater than 1.5e12 through routine experimentation in order to find a dose high enough for systemic administration while still trying to minimize immunotoxicity. Where 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 MPEP2144.05(II).
Regarding claims 10 and 11: Following the discussion of claim 1 above, Ronzitti et al teaches a method of treating Pompe disease comprising administration of an AAV encoding GAA. Ronzitti et al further teaches the AAV production system allows to easily generate pseudotyped AAV vectors composed by the same transgene flanked by the ITRs, most commonly from serotype 2) and any of the available AAV capsid (See Sec. AAV vectors). Thus, in the vector of Ronzitti et al, the transgene (i.e. GAA) is flanked by ITRs and comprises a capsid protein. The ITRs would inherently be either wild-type, mutant, or synthetic.
Additionally, Ronzitti teaches examples in which a tandem liver-neuron promoter is used to drive expression of GAA which reads on the GAA is operatively linked to a promoter.
Regarding claim 13: Following the discussion of claims 1 and 10 above, Ronzitti et al teaches a method of treating Pompe disease comprising administration of an AAV encoding GAA which would inherently increase the amount of GAA (reads on disease gene).
Regarding claim 23: Following the discussion of claim 1 above, Ronzitti, in view of Blumenkranz and Gasmi and Szalay teach a method of treating Pompe disease by administering a viral vector encoding GAA and an antibiotic. The fact that the antibiotic is administered means the antibiotic is administered at least once.
Regarding claim 26: Following the discussion of claim 1 above Ronzitti, in view of Blumenkranz and Gasmi and Szalay teach a method of treating Pompe disease by administering a viral vector encoding GAA and an antibiotic. Ronzitti teaches the administration of the viral vector can be systemic.
Szalay teaches a method of enhancing the effectiveness of a therapeutic virus comprising administering an antibiotic with, before, after or during treatment with a therapeutic virus (See claim 1). Szalay further teaches administration of an antibiotic eliminates commensal gut microbes thereby improving efficacy of viral therapy that is administered systemically (See ¶0217).
Given that Ronzitti et al teaches a method of treatment comprising administration of an AAV and an antibiotic and Szalay teaches using an antibiotic improves viral therapy that is administered systemically by eliminating commensal gut microbes, it would have been prima facie obvious to administer the AAV and antibiotic of Ronzitti systemically. One would have been motivated to administer the AAV and antibiotic systemically because Szalay teaches inclusion of an antibiotic improves the efficacy of systemically administered AAVs. There is a reasonable expectation of success because system administration can be achieved by intravenous injection (See ¶0390 of Szalay).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARISOL A O'NEILL whose telephone number is (571)272-2490. The examiner can normally be reached Monday - Friday 7:30 - 5:00 EST.
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/MARISOL ANN O'NEILL/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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