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 and Applicant’s arguments, filed 09 June 2026, have been entered in full. Claims 1-10, 13-18 are withdrawn from consideration as being drawn to a non-elected invention. Claims 12, 22 and 25 are canceled. Claims 11, 30 and 31 are amended. New claims 34-36 are added. Claims 11, 19-21, 23, 24, 26-36 are under examination.
Priority
Based on an inspection of the submitted English translation of JP 2016-122187 (submitted in application 16/311,484), the Examiner has concluded that some of the subject matter recited in the instant claims are denied benefit to the prior applications.
Instant claims 11, 19-21, 23, 24, 26, 27 and 36 have priority to JP 2016-122187 (filed 6/20/2016). Instant claims 28-35 have priority to 371 of PCT/JP17/22509 (6/19/2017).
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 3/2/2026, 6/9/2026 and 7/24/2026) 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.
Withdrawn Objections And/Or Rejections
The objection to claim 11, as set forth at page 3 of the previous Office Action( 09 February 2026), is withdrawn in view of the amendment (09 June 2026).
The rejection to claims 12, 19, 21-25, 30 and 31 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth at pages 4-5 of the previous Office Action( 09 February 2026), is withdrawn in view of the amendment (09 June 2026).
The rejection to claims 11 and 20 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. (Developmental Immunology, Vol 4:235-246; 1996), as set forth at pages 5-7 of the previous Office Action (09 February 2026), is withdrawn in view of the amendment which now recites the limitations “in a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle” and “selecting the subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle” (09 June 2026).
The rejection to claims 11, 19, 20, 21, 23, 24, 26 and 27 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), as set forth at pages 7-12 of the previous Office Action (09 February 2026), is withdrawn in view of the amendment which now recites the limitations “in a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle” and “selecting the subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle” (09 June 2026).
The rejection to claims 22, 25, 28-33 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. (US 2020/0325237; published Oct. 15, 2020, priority date Dec. 21, 2018), as set forth at pages 12-15 of the previous Office Action (09 February 2026), is withdrawn in view of the amendment which now recites the limitations “in a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle” “selecting the subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle” and Applicant’s arguments regarding the Darimont reference and priority (09 June 2026).
MATTER OF RECORD
The modifications to the claims in the submitted amendment obviated all of the pending arguments. Therefore, Applicants arguments will not be addressed. Please see the New Rejections below.
NEW CLAIM REJECTIONS/OBJECTIONS
Claim Rejections-35 USC § 112(a) or 35 U.S.C. 112 (pre-AIA ), First paragraph, Written description, New Matter
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 11, 19-21, 23, 24, 26-36 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. This is a New Matter Rejection.
The specification as originally filed does not provide support for the invention as now claimed:
A method of delivering a conjugate of an anti-CD71 monoclonal antibody or an antigen-binding fragment thereof with a drug to cardiac muscle and skeletal muscle in a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle, the method comprising: selecting the subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle, and intravenously administering an effective amount of a conjugate to the subject, wherein upon administering, the administered conjugate passes through a layer of vascular endothelial cells to reach the cardiac muscle and/or the skeletal muscle in the subject.
(see claim 11)
Applicant's amendment, filed 09 June 2026, asserts that no new matter has been added and directs support throughout the specification and including for amended claim 11, now canceled claim 12.
Applicant’s arguments have been fully considered but are not found persuasive.
The Examiner has copied canceled claim 12 (see below).
Canceled claim 12: 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.
The Examiner cannot locate the wording or connotation of the instant claims.
That is to say, the Examiner cannot find a teaching of intravenously administering to a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle.
The Examiner cannot find a teaching of a method step in the specification which recites selecting the subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle.
The specification as filed does not provide a written description or set forth the metes and bounds of these "limitations". The instant claims now recite limitations which were not disclosed in the specification as filed, and now changes the scope of the instant disclosure as-filed, resulting in New Matter.
Claims 19-21, 23, 24, 26-36 are included in this rejection insofar as they depend from claim 11 and do not resolve the issue discussed above.
Applicant is required to cancel the new matter in the response to this Office action. Alternatively, Applicant is invited to provide specific written support for the “limitations” indicated above or rely upon the limitations set forth in the specification as filed.
Claim Rejections-35 USC § 112(a) or 35 U.S.C. 112 (pre-AIA ), First paragraph, Enablement
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 11, 19-21, 23, 24, 26-36 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Examiner notes the new limitations to claim 11: “in a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle” and “selecting the subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle”.
The instant claims now encompass a method of treatment because the recited subject population needs drug delivery to the cardiac muscle and/or the skeletal muscle, and the claims recite an active step of selecting those subjects who need said drug delivery to the cardiac muscle and/or the skeletal muscle.
The instant specification states that an object of the present invention is to provide a method for effectively delivering a drug such as a nucleic acid to a tissue or a muscle cell or the like. The specification states that the present inventors have found that a conjugate of an anti-CD71 antibody or an antigen-binding fragment thereof with a drug is excellently delivered to muscle (paras 0021-0022).
The Examples teach the preparation of a conjugate comprising monoclonal antibody anti-CD71 conjugated to the sequences of siRNAs against either ApoB, hypoxanthine-phosphoribosyl-transferase (HPRT) and myostatin (MSTN), and the sequence of siRNA (siNC) which was used as a negative control.
The Examples teach the antibody-siRNA conjugate was able to bind CD71 in an in vitro binding assay.
The Examples teach in vitro silencing wherein anti-CD71-siHPRT conjugate induced silencing in B cells and T cells in vitro and anti-CD71-siApoB conjugate induced silencing in hepatocyte cells in vitro. The specification teaches that in any of the conjugates, maleimide was used as the linker.
The Examples teach intravenously administering anti-CD71-siApoB conjugate to mice. The Examples teach silencing of ApoB in the liver.
The Examples teach intravenously administering anti-CD71-siHRPT conjugate to mice. The Examples teach silencing of HRPT in cardiac muscle and gastrocnemius muscle. The Examples teach CD71 is highly expressed in cardiac and gastrocnemius muscles.
The Examples teach the Effect of anti-CD71 Antibody Fab′-siMSTN in a Peripheral Artery Disease Model. The Examples teach that this model has been used as a PAD model to verify effects of various medicaments. The Examples teach to the mouse, anti-CD71-siMSTN conjugate (or PBS as a control) was administered once a week intramuscularly for four weeks. The Examples teach 7 days after intramuscular administration of anti-CD71 Antibody Fab′-siMSTN to gastrocnemius muscle, mRNA expression level of myostatin decreased in a dose-dependent manner.
Femoral artery ligation (FAL) decreased the mRNA expression level of myostatin but did not alter the muscle weight in gastrocnemius muscle treated with PBS. However, in the model to which clone R17 Fab′-siMSTN was administered, 17% increase in quantity of muscle was observed, compared to the control group to which PBS was administered. When subjected to a running performance test, the untreated PAD model (PBS-administered group) had a total running distance of 1,986 m, while the mouse treated with anti-CD71 antibody Fab′-siMSTN had total running distance of 2,359 m.
The specification fails to provide enablement for the claimed invention for the following reasons:
1. The broadest claims encompass intravenously administering a conjugate comprising anti-CD71 and any drug (or any siRNA drug) to a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle.
However, the art recognizes the unpredictability with respect to employing any siRNA sequence. Wang et al. teach the delivery of siRNA therapeutics. Wang et al. teach RNA interference (RNAi) as a highly efficient regulatory process that causes posttranscriptional gene silencing in most eukaryotic cells and represents a promising new approach for producing gene-specific inhibition and knockouts, and designing new therapeutics. Wang et al. teach siRNA as a short stretch (19-30 nucleotides) of double stranded (ds) RNAs capable of degrading the complementary mRNA in the cytoplasm (page 492). Wang et al. teach that several factors limit the utility of siRNA. Wang et al. teach that siRNA may compete with endogenous RNA for, and cause the saturation of, the miRNA processing pathways. Wang et al. teach that RNA may stimulate innate immune responses and that certain GU-rich sequence motifs result in the secretion of inflammatory cytokines in a cell type- and sequence- specific manner. Wang et al. teach that longer dsRNA (>30 nucleotides) can rapidly induce interferons by activating the evolutionarily conserved mechanisms aimed at combating invading viral pathogens (page 493, right column, 1ˢᵗ full paragraph) (Wang et al. Delivery of siRNA therapeutics: Barriers and Carriers. The AAPS Journal, Volume 12/No 4:492-503; 2010).
The artisan would accordingly have no resort save trial-and-error experimentation to determine which of the astronomically large number of possible drugs or siRNA drugs that could be employed in the claimed method. Such experimentation would be undue for one skilled in the art and it cannot be said that the specification provides the necessary guidance.
2. The instant claims recite “intravenous” administration. However, the Examples only teach intravenously administering anti-CD71-siHRPT conjugate to mice. The Examples teach silencing of HRPT in cardiac muscle and only in gastrocnemius muscle.
Therefore, it would be highly unpredictable that a conjugate comprising anti-CD71 and any drug (or any siRNA or siRNAs that target mRNAs encoded by any of the recited genes) could be intravenously administered to a subject who requires delivery of the drug to the cardiac muscle and/or other types of skeletal muscle. The specification fail to provide this guidance.
3. As was stated above, the instant claims are drawn to intravenously administering an anti-CD71 monoclonal antibody-drug conjugate to a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle and a step of actively selecting the subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle. The claimed method encompasses a method of treating because the recited subject-population needs drug delivery to the cardiac muscle and/or skeletal muscle. Indeed, the instant claims further recite wherein the subject has a disease of the muscle or is suffering from muscular dystrophy.
The Examples teach a Peripheral Artery Disease Animal Model. However, the Example only teach intramuscularly administering an anti-CD71-siMSTN conjugate wherein siMSTN was only located in the gastrocnemius muscle.
In addition, an animal model for peripheral artery disease would not be predictive of an art accepted model for muscular dystrophy or any disease of the muscle.
See wherein Justice et al. teach, “It seems an obvious point, but the model used should be appropriate for the question being addressed”. “An ideal disease model accurately mimics the human condition, genetically, experimentally and/or physically”. Justice et al. teach that in one example, data from human blunt-trauma patients were analyzed together with data from a mouse inbreed strain that had been exsanguinated. Justice et al. teach, “Losing a large amount of blood does not equate to blunt trauma, and so this could be perceived as comparing apples to oranges” (page 101, 2nd column 2nd full paragraph). Justice et al. teach that in a different study, a mouse model was reported to display the key motor symptoms seen in humans with amyotrophic lateral sclerosis (ALD). On the basis of this, the model was used in preclinical trial studies and promising drugs candidates were tested in clinical trials; however, the drugs ultimately failed in humans. It was shown that the particular mouse is a poor genetic and phenotypic model of human conditions. Justice et al. state, “This example illustrates how relevance to the human disease being studied, supported by strong data to validate the use of the model is crucial for clinical translation” (page 102, left column, 1st full paragraph)(Justice et al. "Using the mouse to model human disease: increasing validity and reproducibility, Disease, Models & Mechanisms 9:101-103, 2016).
Due to the inherent unpredictability and the large quantity of experimentation necessary to demonstrate that a conjugate comprising monoclonal anti-CD71 and any drug (or any siRNA or siRNAs that target mRNAs encoded by any of the recited genes) can be intravenously administered to a subject who requires delivery of the drug to the cardiac muscle and/or the skeletal muscle; the lack of direction/guidance presented in the specification regarding same, the absence of working examples directed to same; the complex nature of the invention; the state of the art which teach the unpredictability with respect to employing any siRNA sequence and the state of the art which teaches animal models should accurately mimics the human condition, genetically, experimentally and/or physically; undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
Conclusion
No claims are allowed.
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.
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/R.M.D/Examiner, Art Unit 1647 8/25/2026
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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