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 .
Applicants’ response on 11/03/2025 has been received and 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 Claims 17-19 and 28-30 are withdrawn from consideration, as being directed to a non-elected invention.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.
Claim Amendments
The amendment to the claims filed on 11/03/2025, does not comply with the requirements of 37 CFR 1.121(c) because the amendments fail to show proper markings of changes made to amendments. Claim 10, listed as “Previously Presented” has been amended as follows:
The method of claim 1, wherein the viral vector genome comprises
5’ and 3’ AAV inverted terminal repeats (ITR) sequences, and
Located between the 5’ and 3’ ITRs, a heterologous nucleic acid sequence encoding GAA, wherein the heterologous nucleic acid encoding GAA is operatively linked to a promoter, wherein the ITR is a wild-type (WT) ITR, a mutant ITR, or a synthetic ITR.
Thus, the amendment could be considered non-responsive. However, in the interest of compact prosecution the amendment at issue will not be considered non-responsive. However, any future responses failing to comply with 37 CFR 1.121 will be held non-responsive, and will not be considered.
Status of Prior Rejections/Response to Arguments
RE: Objection to claims 15 and 16
Claims 15 and 16 have been cancelled thus rendering the objection moot.
RE: Rejection of claims 1-4, 8-11, 13, and 23 under 35 U.S.C. 102 over Blumenkranz and Gasmi (WO2017218981A2)
Applicants have amended claim 1 to require that the subject has Glycogen Storage Disease Type II (Pompe Disease), the viral vector expresses a heterologous nucleic acid sequence encoding GAA, and the antibiotic is a member of the tetracycline or macrolides families of antibiotics. Blumenkranz and Gasmi do not teach these limitations. Claims 2-4, 8-11, 13, and 23 depend from claim 1.
The rejection is over claims 1-4, 8-11, 13, and 23 is withdrawn.
RE: Rejection of claims 1-5, 8, 23 and 26 under 35 U.S.C. 102 over Szalay (US20140271549A1).
Applicants have amended claim 1 to require that the subject has Glycogen Storage Disease Type II (Pompe Disease) and that the viral vector expresses a heterologous nucleic acid sequence encoding GAA. Szalay does not teach these limitations. Claims 2-5, 8, 23, and 26 depend from claim 1.
The rejection over claims 1-4, 8, 23, and 26 is therefore withdrawn.
Claim 5 has been canceled thus rendering the rejection over claim 5 moot.
RE: Rejection of claims 1-4, 8-11, 13, 15, 16 and 23 are under 35 U.S.C. 103 over Blumenkranz and Gasmi (WO2017218981A2) in view of Ronzitti et al (Ann Transl Med. 2019).
Applicants have amended claim 1 to require that the subject has Glycogen Storage Disease Type II (Pompe Disease), the viral vector expresses a heterologous nucleic acid sequence encoding GAA, and the antibiotic is a member of the tetracycline or macrolides families of antibiotics. Neither Blumenkranz and Gasmi nor Ronzitti et al teach a method comprising administration of a tetracycline or macrolides antibiotic. Claims 2-4, 8-11, 13 and 23 depend from claim 1.
The rejection over claims 1-4, 8-11, 13, and 23 is therefore withdrawn.
Claims 15 and 16 have been cancelled thus rendering the rejection over claims 15 and 16 moot.
New Rejections
Claim Rejections - 35 USC § 112(b)
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.
Claim 13 is 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 13 recites the limitation "the therapeutic gene" in line 1. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the term “the therapeutic gene” is being interpreted as “GAA”. Appropriate correction is required.
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 the therapeutic gene (GAA) to alter, increase, or decrease 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 but high doses of vector can cause immunotoxicity and Blumenkranz and Gasmi and Szalay teach administration of an AAV along with an antibiotic can reduce immunotoxicity, it would have been prima facie obvious to add an antibiotic to the treatment method of Ronzitti et al in order to reduce toxicity to the AAV and improve treatment for Pompe disease. 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 reduce immunotoxicity to the AAV. There is a reasonable expectation of success because Blumenkranz and Gasmi because Szalay teaches tetracycline and macrolides antibiotics can be used to reduce toxicity.
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
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 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MARISOL ANN O'NEILL/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633