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 with traverse of claims 25 and 30-31 in the reply filed on July 24, 2025 is acknowledged. The traversal is on the ground(s) that there is no search burden as groups I-III overlap with each other as all groups relate to MMACHC. This is not found persuasive because, for instance, a search of a polypeptide encoded by a MMACHC in group I would not likely to contain references pertaining to a detection method for detecting exogenous MMACHC in group III. Hence, separate search and examination for each of groups I-III are required.
The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Claims 13, 15, 18-20, 25, 30-31, and 38-40 are currently pending in the instant application. Claims 13, 15, 18-20, and 38-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Accordingly, claims 25 and 30-31 are under examination on the merits in the instant application.
Claim Objections
Claim 25 is objected to because of the following informalities: “cobalamin C type and deficiency of MMACHC” should be “cobalamin deficiency type C” (see paragraph 0023) or “deficiency of MMACHC” (see paragraph 0065), unless applicant presents evidence that “cobalamin C type and deficiency of MMACHC” is an art-recognized term. Appropriate correction is required.
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 25 and 30-31 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.
The claims recite a “method of treating or preventing…the method comprising administering” and also simultaneously recite “the administration treats the condition in the subject.” As such, the claims recite the broad limitation of “treating or preventing” the recited condition by administrating the polynucleotide as well as the narrower limitation pertaining only to the “treating” such that “the administration treats the condition in the subject.”
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language “treats the condition” is (a) merely exemplary of the remainder of the claims, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
Claims 25 and 30 recite the broad limitations that the at least one condition is “deficiency of MMACHC” or “low levels of MMACHC” and also simultaneously recite multiple narrower limitations within the broad limitations, wherein all of the conditions preceding the broad limitations are characterized by “deficiency of MMACHC” or “low levels of MMACHC”. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language such as “methylmalonic acidemia” is (a) merely exemplary of the remainder of the claims reciting “deficiency of MMACHC” or “low levels of MMACHC”, and therefore not required, or (b) a required feature of the claims.
Claim 25 recites the limitation "the condition" in line 7. There is insufficient antecedent basis for this limitation in the claim. Note that the preceding limitation recites “at least one condition”.
Claim 30 recites the limitation "the condition" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 31 recites the limitation "the condition" in line 8. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112
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 30 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 30 depends from claim 25, wherein claim 25 recites “treating or preventing at least one condition of methylmalonic acidemia, hyperhomocysteinemia, homocystinura, cobalamin C type and deficiency of MMACHC, and low levels of MMACHC in a subject”. As such, claim 25 does not recite “vision loss” as one of “at least one condition”. Hence, claim 30 that recites “vision loss” as being “at least one condition” of claim 25 introduces a new condition not recited in claim 25, thereby failing to further limit the subject matter of claim 25.
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.
For examination purpose, claim 30 will be interpreted as treating vision loss associated with “at least one condition” recited in claim 25.
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.
Claims 25 and 30-31 are 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.
The instant claims comprise a method step of administering a synthetic polynucleotide “encoding MMACHC that is codon-optimized for expression in a human”.
The instant specification does not appear to disclose “expression in a human” required by the claims. That is, there is no structure-function correlation between the structure of codon-optimized sequence, which appears to be SEQ ID NO:2 (“a codon-optimized, synthetic human MMACHC”; see paragraph 0101), and the structure’s function of being optimized “for expression in a human” as opposed to other animals including a mouse exemplified in the instant application.
Regarding the genus of codon-optimized human MMACHC sequences as broadly claimed in the instant case, it is noted that the instant specification at best discloses a single “codon-optimized, synthetic human MMACHC” sequence, which is SEQ ID NO:2. See paragraph 0101. The single species is not a representative number of species reflecting the structural variants encompassed by the genus because SEQ ID NO:2-mediated extended survival of the mouse model of cblC deficiency displaying “eye pathology” and “cblC-related biochemical perturbations” as disclosed in the instant specification cannot be extrapolated to other polynucleotide sequences that are differently codon-optimized. In addition, the extended survival of the mice treated with SEQ ID NO:2 is far from representing the treatment/prevention of various clinical symptoms of all of the recited conditions: methylmalonic acidemia, hyperhomocysteinemia, homocystinura, cobalamin C type and deficiency of MMACHC, low levels of MMACHC, congenital heart defects, neural tube defects, combined methylmalonic acidemia and homocystinuria X type, HCFC1 spectrum defects, hyperhomocystinuria, and vitamin B12 deficiency.
In addition, the “polynucleotide” as broadly recited encompasses both codon-optimized RNA (mRNA) and DNA encoding human MMACHC. It is noted that the single codon-optimized sequence of SEQ ID NO:2 disclosed in the instant application is identified as a DNA sequence. See the sequence listing. The instant specification is completely silent regarding a codon-optimized mRNA sequence encoding human MMACHC, wherein the codon-optimized DNA sequence of SEQ ID NO:2 cannot represent a codon-optimized mRNA sequence.
Regarding treating/preventing “vision loss” as recited in claim 30, the instant specification expressly discloses that mice treated with SEQ ID NO:2 developed, not treated for, “retinopathy” with “a loss of inner and outer photoreceptors and thinning of the outer nuclear layer”. See paragraph 0109. As such, the method of claim 30 is not adequately supported by the specification.
In view of the foregoing, it is concluded that the instant specification fails to adequately and sufficiently describe claims 25 and 30-31 as broadly claimed and the specification fails to reasonably convey that the instant co-inventors had possession of other than the DNA sequence of SEQ ID NO:2 for the synthetic polynucleotide used in the methods of claims 25 and 30-31 as of the filing date sought in the instant case.
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 25 and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Greogory et al. (US 2014/0155468 A1, applicant’s citation) in view of Kim et al. (Theranostics, published on January 1, 2015, 5:86-96) and Fischer et al. (The Journal of Inherited Metabolic Disease, 2014, 37:831-840).
Gregory teaches a method of treating a genetic metabolic disorder including “methylmalonic acidemia” comprising administering a transgene encoding “MMACHC”, thereby increasing the expression of the protein encoded by “MMACHC”, which is defective in methylmalonic acidemia. See paragraphs 0148, 0150; Table A; claims 7-8 and 12.
Gregory does not teach that the transgene encoding MMACHC is a codon-optimized.
Kim teaches that a codon-optimized wild-type human gene sequence encoding a therapeutic protein provides a significantly increased protein expression by “4- to 5.4-fold” compared to a wild-type human gene sequence that is not codon-optimized and also results in an improved therapeutic effect, wherein codon optimization is “performed based on highest usage frequencies in humans”. See pages 89-91; Figures 1(A)-1(C), 2(C), and 4(B).
Fischer teaches that patients having inborn MMACHC gene mutations have “nutritional vitamin B12 deficiency” and develop eye symptoms/problems or “ocular signs” including visual impairment. See pages 832-834; Table 1; Figure 2.
It would have been obvious to one of ordinary skill in the art before the effective filing date to perform codon optimization of the human MMACHC gene sequence and administer the codon-optimized gene sequence when practicing Gregory’s method. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to provide an increased expression of the normal, wild-type MMACHC protein in a subject having methylmalonic acidemia for an improved therapeutic effect, because a codon-optimized wild-type gene sequence encoding a therapeutic protein was known to significantly increase the expression level of the encoded therapeutic protein by “4- to 5.4-fold” compared to a wild-type gene sequence that is not codon-optimized as taught by Kim, who also taught that the codon-optimized wild-type gene sequence administration provides an improved therapeutic effect.
It would also have been obvious to one of ordinary skill in the art before the effective filing date to administer the codon-optimized human MMACHC gene sequence to a patient having MMACHC mutations/deficiency in order to treat the symptoms of visual impairment/loss and the well-known, art-recognized “nutritional vitamin B12 deficiency”, as the symptoms were known to be associated with the inborn MMACHC mutations/deficiency as taught by Fischer.
Accordingly, claims 25 and 30-31 taken as a whole would have been prima facie obvious before the effective filing date.
Claims 25 and 30-31 are rejected under 35 U.S.C. 103 as being unpatentable over Gizicki et al. (Ophthalmology, 2014, 121:381-386) in view of Chandler et al. (Molecular Therapy, 2010, 18:11-16, applicant’s submitted copy is “Author Manuscript”; original article is attached) and Kim et al. (Theranostics, published on January 1, 2015, 5:86-96).
Gizicki teaches that cobalamin C disease (cblC) is “an autosomal recessive disease” that is “most common inborn error of vitamin B12 (cobalamin) metabolism” caused by mutations “in the MMACHC gene (Online Mendelian Inheritance in Man, 609831)” and “is characterized by the impaired conversion of vitamin B12 into its 2 active forms”, “leading to methylmalonic aciduria and increased plasma homocysteine.” See page 381.
Gizicki reports that cblC patients with MMACHC gene mutations develop “poor visual function as well as pigmentary retinopathy, maculopathy, and nystagmus” and “progressive deterioration of both photopic and scotopic ERG results”. See pages 382-385; Tables 1-2.
Gizicki teaches, “Current medical treatment of cblC disease usually does not result in complete normalization of methionine, homocysteine, or methylmalonic acid levels and does not ensure normal ophthalmologic or neurologic outcomes, even if started prenatally.” See page 385.
Gizicki does not teach administering a codon-optimized human MMACHC DNA sequence to cblC patients as a treatment option.
Chandler teaches a method of “gene therapy” for treating a genetic metabolic disorder methylmalonic acidemia (MMA) that is “an autosomal recessive inborn error” causing deficient enzymatic activity of the mutated gene, wherein administration of a synthetic wild-type gene provides gene therapy by restoring the enzymatic activity of the wild-type gene, which resulted in extended survival of Mut-/- mice, wherein the gene therapy “should be immediately translatable to a human gene therapy trial”. See the entire reference including pages 11-12.
Chandler teaches that MMA can be caused by defective “metabolism of cobalamin.” See page 11.
Kim teaches that a codon-optimized wild-type human gene sequence encoding a therapeutic protein provides a significantly increased protein expression by “4- to 5.4-fold” compared to a wild-type human gene sequence that is not codon-optimized and also results in an improved therapeutic effect, wherein codon optimization is “performed based on highest usage frequencies in humans”. See pages 89-91; Figures 1(A)-1(C), 2(C), and 4(B).
It would have been obvious to one of ordinary skill in the art before the effective filing date to provide gene therapy comprising a codon-optimized human wild-type MMACHC gene to a cblC patient. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to provide an exogenous, synthetic human wild-type MMACHC gene to the patient having endogenously deficient human wild-type MMACHC causing defective metabolism of vitamin B12 (cobalamin), wherein the exogenous, synthetic human wild-type MMACHC gene increases and restores metabolism of vitamin B12 in the cblC patient, because there was an art-recognized need for a new effective medical treatment for the autosomal recessive inborn disease caused by MMACHC mutations/deficiency as evidenced by the fact that the “medical treatment of cblC disease usually does not result in complete normalization of methionine, homocysteine, or methylmalonic acid levels and does not ensure normal ophthalmologic or neurologic outcomes, even if started prenatally” as reported by Gizicki, and because gene therapy that administers a synthetic wild-type gene sequence to a subject having “an autosomal recessive inborn error” resulting in a genetic metabolic disorder that can be caused by defective “metabolism of cobalamin” was an art-recognized treatment option that was deemed to be “immediately translatable to a human gene therapy trial” as taught by Chandler. When providing gene therapy to restore and increase the human wild-type MMACHC gene in the cblC patient lacking the MMACHC gene, one of ordinary skill in the art would have been motivated to codon-optimize the human wild-type MMACHC gene in order to provide a significantly increased expression of the normal, wild-type MMACHC protein in the cblC patient having “inborn error of vitamin B12”, “methylmalonic aciduria and increased plasma homocysteine”, and “poor visual function”, thereby providing improved therapeutic effects compared to the sequence that is not codon-optimized, because a codon-optimized wild-type gene sequence encoding a therapeutic protein was known to significantly increase the expression level of the encoded therapeutic protein by “4- to 5.4-fold” compared to a wild-type gene sequence that is not codon-optimized as taught by Kim, who also taught that the codon-optimized wild-type gene sequence administration provides an improved therapeutic effect.
Accordingly, claims 25 and 30-31 taken as a whole would have been prima facie obvious before the effective filing date.
Conclusion
No claim is allowed.
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/DANA H SHIN/Primary Examiner, Art Unit 1635