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 .
Status of Application, Amendments and/or Claims
The amendment, filed 27 November 2024, has been entered in full. Claims 3-10, 16 and 17 are amended.
Applicant’s election without traverse of Group II (claims 11 and 12, drawn to a method for delivering a conjugate of anti-CD71 antibody or an antigen binding fragment thereof with a drug to cardiac muscles or skeletal muscles), in the reply filed on 05 November 2025, is acknowledged.
Claims 1-10, 13-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05 November 2025.
The amendment, filed 05 November 2025, has been entered in full. Claim 11 is amended. New claims 19-33 are added. Applicant states that new claims 19-33 correspond to elected Group II. Claims 11, 12, 19-33 are under examination.
Foreign Priority
Acknowledgment is made of Applicant's claim for foreign priority under 35
U.S.C. 119(a)-(d). The certified copy JP 2016-122187 (filed 6/20/16) has been filed in the instant application. The English translation of documents of JP 2016-122187 was submitted in application 16/311,464.
Priority
Based on an inspection of the English translation of JP 2016-122187, the Examiner has concluded that some of the subject matter recited in the instant claims are denied benefit to the prior applications.
The Examiner does not see support in the English translation of JP 2016-122187 for the limitations recited in claim 22 (except for a myostatin gene), claim 25 (except for a myostatin gene) and claims 28-33.
Therefore, instant claims 11, 12, 19-21, 23, 24, 26 and 27 have priority to JP 2016-122187 (filed 6/20/2016). Instant claims 22, 25, 28-33 have priority to application 16/311,464 (filed 2/14/2019).
If Applicant disagrees with the Examiner’s assessment, Applicant is requested to specifically point to support in JP 2016-122187 for the limitations.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 4/16/24 and 4/9/25) were received and comply with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. They have been placed in the application file and the information referred to therein has been considered as to the merits.
Claim Objections
Claim 11 is objected to because of the following informalities:
Claim 11 has a typo; “a conjugate of of” should be “a conjugate of”. 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 12, 19, 21-25, 30 and 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.
Claim 12 is indefinite because of the recitation, ”An anti-CD71 antibody or antigen-binding fragment thereof for use in delivering a drug to at least one selected from cardiac muscle and skeletal muscle”. See the teaching of MPEP 2173.05(q) "Use" Claims: “Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph”.
Claims 19 and 23 are indefinite because they recite the limitation "anti-CD71 monoclonal antibody". The claims depend from claim 11, which recites “anti-CD71 antibody”. There is insufficient antecedent basis for the limitation “monoclonal” in the claims. Claims 21, 22, 24, 25, 27-33 are included in this rejection insofar as they depend from claims 19 and 23 and do not resolve the issue discussed above.
Claims 22, 25, 30 and 31 are indefinite because the difference between “dystrophin gene” (see claims 22 and 25) and “dystrophin that causes muscular dystrophy” (see claims 30 and 31) is unclear and the specification does not provide a standard for ascertaining the requisite degree. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 22 and 25 are indefinite because they recite two Markush Groups. Additionally, “myostatin gene” is recited in both Groups.
Claims 22 and 25 are indefinite because they recite the acronyms SMN2, DMPK, SOC1, PABPN1, cPLA2, AMPA, FOXO, C90rf72, ActRIIB, DUX4, NLRP3, ApoA, STIM1, EGF1, VEGF-A and serca2a, which have not been defined in the claims. Acronyms should be defined upon their first use in a claim. The presence of an undefined acronym renders a claim indefinite.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 11 and 20 are rejected under 35 U.S.C. 102(a1) and 35 U.S.C. 102(a2) as being anticipated by Montefeltro et al. (US 2012/0322991; published Dec 20, 2012) as evidenced by Crook et al. (Reference submitted by Applicant; Developmental Immunology, Vol 4:235-246; 1996).
Montefeltro et al. teach a conjugate comprising (i) a nucleic acid which is complementary to a target nucleic acid sequence and which expression prevents or reduces expression of the target nucleic acid and (ii) a selectivity agent which is capable of binding with high affinity to a neurotransmitter transporter (abstract).
Montefeltro et al. teach the term "conjugate", as used herein, refers to any compound resulting from the covalent attachment of two or more individual compounds. In the present invention, conjugate refers to a molecule comprising a nucleic acid a selectivity agent which are covalently coupled, being said coupling direct or via a linking compound. The terms "covalent coupling" or "covalent attachment" mean that the nucleic acid and the selectivity agent are either directly covalently joined to one another, or else are indirectly covalently joined to one another through an intervening moiety or moieties, such as a linker, or a bridge, or a spacer, moiety or moieties (paras 0085-0086)(applies to claim 20). Montefeltro et al. teach nucleic acids of the invention include siRNA (paras 0122, 0123, 0125 and 0128)(i.e. drug applies to claims 11 and 20).
Montefeltro et al. teach that another modification of the conjugates of the invention involve chemically linking to the nucleic acid one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the nucleic acid (paras 0253-0254). Montefeltro et al. teach that such moieties include but are not limited to humanized monoclonal antibodies that bind to the human transferrin receptor or anti-human transferrin receptor (TfR) monoclonal antibody A24 (para 0256)(applies to claim 11).
CD71 is also known as transferrin receptor as evidenced by Crook et al. (see abstract).
Montefeltro et al. teach that conjugate can be delivered to a subject by a variety of routes including systemically, e.g., by intravenous administration (para 0321)(applies to claim 11).
The Examiner notes that the limitations “to cardiac muscle and skeletal muscle”, “whereby the conjugate passes through a layer of vascular endothelial cells to reach the cardiac muscle and skeletal muscle in the subject” and “inhibits the target gene expression in the skeletal muscle cells or cardiac muscle cells of the subject for 14 days after an intravenous injection of the conjugate to the subject” are not positive active steps of the claimed method.
The recited limitations are functional language that describes a property that occurs when the conjugate is intravenously administered to a subject. Because Montefeltro et al. teach the methods steps recited in claims 11 and 20, those recited functional effects would be inherent to the method teaching the recited steps.
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.
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.
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.
1. Claims 11, 19, 20, 21, 23, 24, 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Montefeltro et al. (US 2012/0322991; published Dec 20, 2012) in view of Ma et al. (US 2017/0216452; published Aug 3, 2017, priority date Nov. 30, 2015), as evidenced by Crook et al. (Developmental Immunology, Vol 4:235-246; 1996).
Montefeltro et al. teach a conjugate comprising (i) a nucleic acid which is complementary to a target nucleic acid sequence and which expression prevents or reduces expression of the target nucleic acid and (ii) a selectivity agent which is capable of binding with high affinity to a neurotransmitter transporter (abstract). Montefeltro et al. teach the term "conjugate", as used herein, refers to any compound resulting from the covalent attachment of two or more individual compounds. In the present invention, conjugate refers to a molecule comprising a nucleic acid a selectivity agent which are covalently coupled, being said coupling direct or via a linking compound. The terms "covalent coupling" or "covalent attachment" mean that the nucleic acid and the selectivity agent are either directly covalently joined to one another, or else are indirectly covalently joined to one another through an intervening moiety or moieties, such as a linker, or a bridge, or a spacer, moiety or moieties (paras 0085-0086)(applies to claim 20). Montefeltro et al. teach nucleic acids of the invention include siRNA (paras 0122, 0123, 0125 and 0128)(i.e. drug applies to claim 11). Montefeltro et al. teach that another modification of the conjugates of the invention involve chemically linking to the nucleic acid one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the nucleic acid (paras 0253-0254). Montefeltro et al. teach that such moieties include but are not limited to humanized monoclonal antibodies that bind to the human transferrin receptor or anti-human transferrin receptor (TfR) monoclonal antibody A24 (para 0256)(applies to claim 11).
CD71 is also known as transferrin receptor as evidenced by Crook et al. (see abstract).
Montefeltro et al. teach that conjugate can be delivered to a subject by a variety of routes including systemically, e.g., by intravenous administration (para 0321)(applies to claim 11). The Examiner notes that the limitations “to cardiac muscle and skeletal muscle”, “whereby the conjugate passes through a layer of vascular endothelial cells to reach the cardiac muscle and skeletal muscle in the subject” and “inhibits the target gene expression in the skeletal muscle cells or cardiac muscle cells of the subject for 14 days after an intravenous injection of the conjugate to the subject” are not positive active steps of the claimed method. The recited limitations are functional language that describes a property that occurs when the conjugate is intravenously administered to a subject. Because Montefeltro et al. teach the methods steps recited in claims 11 and 20, those recited functional effects would be inherent to the method teaching the recited steps.
In summary, Montefeltro et al. teach a conjugate comprising a humanized monoclonal antibody that binds to the human transferrin receptor or an anti-human transferrin receptor (TfR) monoclonal antibody A24 that is covalently linked siRNA. Montefeltro et al. teach the linkage can be either directly covalently joined to one another, indirectly covalently joined to one another through an intervening moiety or moieties, such as a linker, or a bridge, or a spacer, moiety or moieties.
Montefeltro et al. do not teach wherein the linker is a non-cleavable linker comprising a maleimide group at the end of the linker and/or a valine-citrulline cleavable linker. Montefeltro et al. do not teach Fab or Fab’ antibody fragments.
Ma et al. teach an antibody or an antigen-binding fragments thereof that comprises a substituted cysteine for site-specific conjugation (abstract). Ma et al. teach a conjugate comprising an antibody or antigen-binding fragment thereof linked to a therapeutic agent, wherein said therapeutic agent is siRNA (para 0044, E95)(applies to claims 19 and 23). Ma et al. teach an “antigen-binding fragment” includes a Fab fragment (para 0382)(applies to claim 26 and 26). Ma et al. teach that antibody drug conjugates (ADCs) are prepared using a linker to link or conjugate a drug to an antibody. Ma et al. teach suitable linkers include cleavable linkers (such as valine-citrulline, also known as val-cit or vc), non-cleavable linkers and covalent linking (para 0279-0285 and Table 3). Ma et al. teach an antibody-linker-drug comprising a maleimide group or a hydrolyzed maleimide group. Ma et al. teach that maleimides are considered to be specific to sulfhydryl groups (paras 0285, 0287-0290)(i.e. sulfhydryl groups on antibodies; applies to claim 19). Ma et al. teach wherein the linker comprises 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vc-PAB)(page 6, E103 and para 0291)(i.e. valine-citrulline cleavable linker and maleimide group; applies to claim 23). Ma et al. teach that the agents are formulated for administration by injection (e.g., intraperitoneally, intravenously, subcutaneously, intramuscularly, etc.)(para 0364). Because Ma et al. teach the methods steps recited in claims 19 and 23, those recited functional effects would be inherent to the method teaching the recited steps (applies to claims 19, 21, 23 and 24).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of delivering to a subject a conjugate comprising anti-CD71 antibody-linker-siRNA, as taught by Montefeltro et al., by using a non-cleavable linker comprising a maleimide group at the end of the linker or a valine-citrulline cleavable linker comprising a valine-citrulline peptide moiety and a maleimide group, as taught by Ma et al. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success for the following reasons.
Ma et al. teach that although antibody-drug conjugates (ADCs) hold promise for cancer therapy, cytotoxic drugs are generally conjugated to the antibodies via lysine side chains or by reducing interchain disulfide bonds present in the antibodies to provide activated cysteine sulfhydryl groups. Ma et al. teach that this non-specific conjugation approach has numerous drawbacks. Drug conjugation to antibody lysine residues is complicated by the fact that there are many lysine residues in an antibody available for conjugation. Ma et al. teach that since the optimal number of drug to antibody ratio (DAR) is much lower, lysine conjugation often generates a very heterogeneous profile. In addition, many lysines are located in critical antigen binding sites of CDR region and drug conjugation may lead to a reduction in antibody affinity. Ma et al. teach that genetic engineering of free cysteine residues has enabled site-specific conjugation with thiol-based chemistries.
Claims 22, 25, 28-33 are rejected under 35 U.S.C. 103 as being unpatentable over Montefeltro et al. in view of Ma et al., as evidenced by Crook et al., as applied to claims 11, 19, 21, 23 and 24 above, and further in view of Darimont et al. (Reference submitted by Applicant, US 2020/0325237; published Oct. 15, 2020, priority date Dec. 21, 2018).
Applicant is reminded that the subject matter recited in claims 22, 25, 28-33 have priority to Feb. 14, 2019.
The teachings Montefeltro et al., Ma et al., as evidenced by Crook et al. are described above. The combined references do not teach wherein the siRNA targets DUX4, dystrophin or DMPK.
Darimont et al. teach anti-transferrin receptor antibody conjugates. Darimont et al. teach methods of delivering a payload utilizing an anti-transferrin receptor antibody (abstract and paras 0003-0005). Darimont et al. teach in certain embodiments, the anti-transferrin receptor antibody conjugate comprises an anti-transferrin receptor antibody and a payload, wherein the payload is a polynucleic acid molecule comprising siRNA. Darimont et al. teach the anti-transferrin receptor antibody is conjugated to siRNA through a linker (para 0007). Darimont et al. teach in some instances, the linker is a cleavable linker. In other instances, the linker is a non-cleavable linker (paras 0309 and 0317). Darimont et al. teach in some embodiments, the linker comprises sulfhydryl cross-linkers comprising maleimide. Darimont et al. teach in some embodiments, the linker comprises a maleimide group. also referred to as a maleimide spacer (paras 0313-0316). Darimont et al. teach in some embodiments, the linker comprises one or more of a maleimide group, a peptide moiety, and/or a benzoic acid group, in any combination. In some embodiments, the linker comprises a combination of a maleimide group, a peptide moiety, and/or a benzoic acid group. In some instances, the maleimide group is maleimidocaproyl (mc). In some instances, the peptide group is val-cit. In some instances, the linker comprises a mc-val-cit group. (paras 0317 and 0319). Darimont et al. teach the pharmaceutical formulations described herein are administered to a subject by multiple administration routes, including intravenously (para 0355).
Darimont et al. teach in some embodiments the polynucleic acid molecule described herein hybridizes to a target sequence of DMPK (para 0161)(applies to claims 22, 25, 32 and 33). Darimont et al. teach in some instances, the polynucleic acid molecule hybridizes to a target region of an incorrectly spliced mRNA which results in a disease or disorder such as Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy. In some instances, the polynucleic acid molecule targets an exon that is mutated in the DMD gene that causes Duchenne muscular dystrophy (paras 0162, 0163, 0327 and 0349)(applies to claims 22, 25, 30 and 31). Darimont et al. teach improperly spliced or partially spliced mRNA in some instances causes a neuromuscular disease or disorder such as Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy. Darimont et al. teach Duchenne muscular dystrophy have been shown to involve mutations in the DMD gene, which encodes the protein dystrophin. Darimont et al. teach facioscapulohumeral muscular dystrophy has been shown to involve mutations in double homeobox, 4 (DUX4) gene (paras 0353 and 0354)(applies to claims 22, 25, 28-31).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a method of delivering to a subject a conjugate comprising anti-CD71 antibody-linker-siRNA comprising a non-cleavable linker comprising a maleimide group at the end of the linker or a valine-citrulline cleavable linker comprising a valine-citrulline peptide moiety and a maleimide group, as taught by Montefeltro et al. and Ma et al., by conjugating siRNA that targets DUX4, dystrophin or DMPK, as taught by Darimont et al.
One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications and expect success because Darimont et al. teach using anti-CD71 antibody-linker-siRNA in treatments for Duchenne muscular dystrophy and facioscapulohumeral muscular dystrophy wherein the siRNA hybridizes to a target region of an incorrectly spliced mRNA in the DMPK gene, DUX4 gene and/or dystrophin gene.
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 2/4/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647