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 .
Election/Restrictions
Applicant’s election without traverse of Group I ( encompassing claims 1-3, 5-6, 10, 22-23, 27, 39, 42, 45-46, 51, 55, 58-60, 71, 73, 77, 81, and 83) and species elections of (heterologous polynucleotide is encoding for a polypeptide, a protease (i.e., claim 22) wherein the protease is a cysteine protease comprising IdeS (i.e., claim 39); an anti-FcRn antibody (i.e., claim 5); the diagnostic and prognostic measures are to be performed following treatment, and the amount of IgG is to be measured (i.e., claims 55, 58-60, and 71); a blood clotting disorder (i.e., claim 73); and a Factor VIII or Factor IX polypeptide (i.e., claim 77)); in the reply filed on 08/07/2025 is acknowledged.
Claims 42, 81,83, and 88 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/07/2025. Therefore, claims 1-3,5-6,10,22-23,27,39, 45-46, 51, 55, 58-60,71,73, and 77 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application provisional application 62964565, filed on 01/22/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-6, 10, 45-46, 51,55, 58-60,71, 73, and 77 are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al ( US 2011/0059889 A1), as evidenced by Murphy et al ( Journal of Medical Virology, 2009).
Regarding claims 1 and 45, Mezo et al teach a method of enhancing gene therapy treatment in a subject. The method involves making and using an anti-FcRn agent ( i.e. a peptide) that can be administered in combination with a gene therapy vector to enhance the benefit of the encoded therapeutic protein by reducing the levels of IgG antibodies produced against the gene therapy vector or the therapeutic polypeptide. According to Mezo et al, the administered peptide is capable of binding to FcRn preventing the FcRn from binding to the Fc portion of an IgG Molecule. Mezo et al further state that “ the gene therapy vector may be, e.g., a viral vector such as adenovirus and adeno associated virus”. (See paragraphs [0046]; [0260]). It is noted that the examples in Mezo et al’s disclosure are primarily directed to methods of making and using the anti-FcRn agent, and none of them show the coadministration of the anti-FcRn agent in combination with a gene therapy vector. However, as stated above, Mezo et al’s disclosure includes embodiments teaching a method of enhancing gene therapy treatment that involves coadministration of the anti-FcRn agent with the gene therapy vector. Therefore, the teachings of Mezo et al render obvious claim1.
Regarding claim 2, Mezo et al state that “ Diseases that can be treated using gene therapy include, but are not limited to, cystic fibrosis, hemophilia, PRCA, muscular dystrophy, or lysosomal storage diseases, such as, e.g., Gaucher's disease and Fabry's disease”. It should be noted that, cystic fibrosis, muscular dystrophy, Gaucher's disease and Fabry's disease are all caused by a loss of function or activity of a protein, and the gene therapy is the supplemental gene. Therefore, the teachings of Mezo et al render obvious claim 2. (See paragraph [0260]).
Regarding claim 3, Mezo et al state that the “ The inhibition of IgG binding to FcRn reduces IgG serum half-life by preventing IgG recycling”. (See paragraph [0009])
Regarding claim 5, Mezo et al teach a method of making a peptide that may be used to reduce the recycling of IgG in combination of gene therapy. Furthermore, Mezo et al state that “ One example of a method of blocking IgG Fc binding to FcRn involves the generation of blocking antibodies to FcRn”. Therefore, the teachings of Mezo et al also render obvious the use of anti-FcRn antibody in combination with gene therapy to reduce the recycling of IgG antibodies. (See paragraph [0009]).
Regarding claim 6, Mezo et al teach that the reducing agent (i.e. peptide) can be administered in combination with a gene therapy vector to enhance the benefit of the encoded therapeutic protein. This reads on step (c) of instant claim i.e. the reducing agent and the gene therapy vector are administered at the same time. (See paragraph [0260]).
Regarding claim 10, Mezo et al do not teach the time interval or the sequence of administering step (b) relative to step (a) as recited in instant claim. However, it is well recognized in the art that it is prima facie obvious for one of ordinary skill in the art to use routine experimentation to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05. The instant application demonstrates that these quantities are a result-effective variables that can be arrived at by routine experimentation. Absent evidence to the contrary and the claim is considered obvious.
Regarding claim 46, Mezo et al teach that the anti-FcRn agent can be administered in combination with a gene therapy viral vector, such as an AAV vector, to reduce the level of the IgG antibodies that are responsible for decreasing the bioavailability of a gene therapy vector. (See paragraph [0260]). While Mezo et al do not explicitly state that AAV vector comprises capsid proteins to which the IgG binds; however, all AAV vectors comprise of capsid proteins, and it is known in the art that subjects exposed to AAV vectors will develop IgG responses to AAV capsid of all four IgG subclasses, as evidenced by Murphy et al ( See abstract). Therefore, the teachings of Mezo et al meet the requirement of step (b) of instant claim.
Regarding claim 51, Mezo et al teach that co-administration of a peptide, that is capable of binding FcRn receptor, with gene therapy vector would enhance the efficacy of gene therapy treatment in a subject, when the subject may have or acquire IgG antibodies to the viral vector or the therapeutic polypeptide. Therefore, the teachings of Mezo et al meet the requirements of the instant claim. (See paragraph [0260]).
Regarding claims 55- 60 and 71, According to Mezo et al “ The result of administering a composition comprising of a peptide that binds to the FcRn receptor is that the half-life of soluble IgG in the serum of the subject is reduced compared to the half-life of lgG in the serum of the subject prior to administration of the peptide”. It is clearly obvious that the method of Mezo et al also employs the diagnostic measures recited in instant claims 55 , 58, and 71. Furthermore, a person skilled in the art could have easily confirmed the level of IgG that binds to the gene therapy vector or the therapeutic polypeptide based on the description disclosed by Mezo et al and the available common technical knowledge. ( See paragraph [0044]). Mezo et al demonstrate that administering the peptide reduces the half-life of the IgG in the subject’s serum. In one embodiment, Mezo et al teach that the decrease in the serum concentration of human IgG is at least 25%, this reads on claim 59. ( See paragraph [0045]). Mezo et al do not specify a specific viral neutralization percentage to be obtained by administering a composition comprising of the peptide, as recited in claim 60. However, it is well recognized in the art that it is prima facie obvious for one of ordinary skill in the art to use routine experimentation to discover an optimum value of a result effective variable. The instant application demonstrates these quantities are a result-effective variables that can be arrived at by routine experimentation, as they are dependent on the subject’s response to the therapy and may differ from one subject to another.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05. Absent evidence to the contrary and the claims are considered obvious.
Regarding claims 73 and 77, Mezo et al’s method may be used for the treatment of blood clotting disorder. Mezo et al also teach that the therapeutic protein (i.e. the heterologous polynucleotide encoding the therapeutic protein) may be a clotting factor selected from factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, factor XIII, etc. (See paragraphs [0249] ; [0258], and claim 120).
Claims 22-23,27,39, are rejected under 35 U.S.C. 103 as being unpatentable over Mezo et al ( US 2011/0059889 A1). as applied to claims 1-6, 10, 45-46, 51,55, 58-60,71, 73, and 77 above, and further in view of Johansson et al ( PLOS One, 2008) and Kjellman et al ( WO 2016/128559 A1) .
Regarding claims 22 and 39, the teachings of Mezo et al are set forth above. Mezo et al render obvious a method of enhancing gene therapy treatment in a subject by co-administering a peptide capable of binding the FcRn receptor in combination with a gene therapy vector to reduce the level of the IgG antibodies responsible for decreasing the bioavailability of a gene therapy vector or the therapeutic polypeptide. However, Mezo et al do not teach the combined administration of a protease that can bind and degrade the IgG antibodies that bind to the viral vector or the therapeutic protein.
Johansson et al teach that IdeS is a proteolytic enzyme produced by the bacterial pathogen Streptococcus pyogenes, which cleaves IgG with a unique degree of specificity. (See abstract). Johansson et al demonstrate that the in vitro administration of 20 mg of IdeS can specifically and efficiently cleave IgG in human blood in 15 minutes. (See Fig,1, lane 2). Johansson et al, further demonstrate that the in vivo administration of 5 mg of IdeS in the blood stream of rabbits, via intravenous injection, efficiently cleaves IgG in 6 hours with no side effects. ( See Fig.3). Johanson et al suggest that IdeS could be used to treat IgG-driven diseases in humans. (See abstract). However, Johansson et al do not teach the coadministration of IdeS in combination with gene therapy viral vector to enhance the clearance and degradation of antibodies that bind to the viral vector or the therapeutic polypeptide.
Kjellman et al teach methods of making and using a modified variant of IdeS for the treatment of diseases or conditions mediated by IgG. According to Kjellman et al, gene therapy treatment is one of the conditions that could benefit from the usage of IdeS. For example, Kjellman et al, disclose that the modified IdeS can be administered in combination with a gene therapy vector to enhance the efficacy of gene therapy treatment in a subject. The method of Kjellman et al comprises of :
(a) administering to the subject the modified IdeS ; and
(b) subsequently administering a therapeutic agent to the subject; such as gene therapy viral vector.
According to Kjellman et al, the amount of modified IdeS administered must be sufficient to cleave substantially all IgG molecules present in the subject’s plasma; and steps (a) and (b) should be separated by a time interval which is sufficient to cleave substantially all IgG molecules present in the plasma of the subject. ( See Abstract, page 5-lines 30-33, and page 6-lines 1-7.
Taken together, claims 22 and 39 is combining prior art elements according to known methods to yield predictable results, namely the predictable result being the enhanced efficacy of gene therapy following the coadministration of anti-FcRn agent and IdeS in combination with gene therapy vector. Because Mezo et al teach the co-administration of anti-FcRn agent in combination with gene therapy vector to enhance the efficacy of gene therapy treatment in a subject, but fail to teach the coadministration of a cysteine protease such as the IdeS to further enhance the degradation and clearance of the IgG antibodies which would develop against the gene therapy vector or the therapeutic protein. Johanson et al demonstrate that the IdeS can specifically and efficiently cleaves all IgG present in a subject’s blood sample without causing any side effect, and further suggest that IdeS could be employed to treat IgG-driven diseases in humans, but fails to teach or suggest its use in gene therapy. However, Kjellman et al disclose that a modified variant of IdeS maybe used in combination with gene therapy to enhance the clearance and degradation of IgG antibodies that bind the viral vector or the therapeutic protein. Therefore, a person of ordinary skill in the art, seeking to enhance the efficacy of gene therapy, would be motivated to combine the teachings of Mezo et al and Johanson et al and use a combination therapy comprising of administering an anti-FcRn agent, as disclosed by Mezo, and IdeS, as disclosed by Johansson, in combination with gene therapy vector to enhance the clearance and degradation of IgG present in the subject’s, thereby reducing the bioavailability of the viral vector or the therapeutic peptide. A person of ordinary skill in the art who has reviewed Mezo, could have come across Johansson and Kjellman and immediately noticed the
strong possibility of using proteases, such as the IdeS or the modified variant of IdeS, in combination with anti-FcRn agent, would have the predictable result of enhancing the efficacy of gene therapy by promoting the degradation of all IgG subclasses that binds the vector or the therapeutic peptide.
Regarding claims 23 and 27, following the discussion of claim 22 above. The combined teachings of Mezo, Kjellman, and Johanson render obvious the combined administration of anti-FcRn agent and IdeS in combination with a gene therapy vector to enhance the efficacy of gene therapy treatment. Claims 23 and 27 recites the sequence and the time interval at which the IdeS is administered relative to the administration of anti-FcRn agent and the gene therapy vector. The instant application demonstrates that these quantities are a result-effective variables that can be arrived at by routine experimentation, as they are dependent on the subject’s response to the therapy and may differ from one subject to another. Therefore, it is prima facie obvious for one of ordinary skill in the art to use routine experimentation to discover an optimum value of a result effective variable.
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05. Absent evidence to the contrary and the claims are considered obvious.
Conclusion
No claim is allowed.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638