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 .
Application Status
This action is written in response to applicant’s correspondence received 12/19/2023. Claims 1-138 are currently pending. Claims 1-4, 6, 41-50, 74-78, and 135 are examined herein. Claims 5, 7-40, 51-73, 79-134, and 136-138 are objected to for being in improper form (see below) and have not been treated on the merits.
Claim Objections
Claims 5, 7-40, 51-73, 79-134, and 136-138 are objected to under 37 CFR 1.75(c) as being in improper form because they are all multiple dependent claims which depend from other multiple depend claims. A multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
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 1-4, 6, 42 and 44 are rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by WIPO Publication 2020198697 to Yong (of record, hereinafter ‘Yong’, published 10/01/2020, priority filing date 03/28/2019).
The applied reference has a common applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Regarding claim 1, Yong teaches a method for treating amyloidosis associated with TTR (ATTR) in a human subject, comprising systemically administering to the human subject a LNP composition comprising an effective amount of:an mRNA encoding a Cas nuclease, and a guide RNA that targets the TTR gene, wherein the administration of the composition reduces serum TTR relative to baseline serum TTR (see claims 3, 6, 7, 27, 36, 37, 45-47; please note that claim 47 ultimately depends from claim 3 via claims 6, 7, 27, 36, 37, 45 and 46, and therefore includes all the limitations of the preceding claims).
Please note that Yong considers “infusion”, as recited in claim 6, to be a form of parenteral administration (¶ [00492]). As evidenced by Verma, parenteral administration is considered a form of systemic administration (Verma et al. Routes of Drug Administration. International Journal of Pharmaceutical Studies and Research. v11, July 2020. Accessed via web on 05/29/2026 at https://romanpub.com/resources/ijpsr%20v11-2020-7.pdf). Therefore, by Yong’s definition and the plain meaning of parenteral administration in the art, Yong’s “infusion” is
Regarding claims 2 and 3, Yong teaches wherein the ATTR is hereditary or wild type transthyretin amyloidosis (claim 46).
Regarding claim 4, Yong teaches wherein the ATTR is hereditary (familial) transthyretin amyloidosis with polyneuropathy (see claim 48).
Regarding claim 6, wherein the ATTR is wildtype transthyretin amyloidosis with cardiomyopathy.
Regarding claims 42 and 44, these claims all recite methods of in vivo editing of the TTR gene or treating ATTR in human subjects, comprising systemically administering a LNP composition comprising an mRNA encoding a Cas nuclease, a guide RNA that targets the TTR gene, and editing the gene at the target site in a hepatocyte. The claims only differ in the recited outcomes: claims 41 and 43 recite wherein administration results in a change in a level of a biosafety metric in the subject that is acceptable as compared to baseline, and claims 42 and 44 recite wherein administration results in clinically significant improvement in a clinical metric in the subject compared to baseline. Claim 50 of Yong teaches, “50. The method or composition for use of any one of claims 2-49, wherein after administration the subject has an improvement, stabilization, or slowing of change in symptoms of sensorimotor neuropathy, and/or the subject has an improvement, stabilization, or slowing of change in symptoms of congestive heart failure.”.
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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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.
Claims 41, 43, 45-47, 49-50, 74, 77, and 135 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication 2020198697 to Yong (cited above) in view of Ding (Ding et al. Establishment of a liver fibrosis model in cynomolgus monkeys. Experimental and Toxicologic Pathology 66 (2014) 257–261.).
Yong teaches methods of editing TTR in vivo/treating human subjects with ATTR (a monogenic disorder) comprising administration of a LNP composition comprising a mRNA encoding a Cas nuclease, a guide RNA that targets a gene in the liver (TTR), and editing the gene, as applied to claims 1-4, 6, 42 and 44 in the rejection of those claims under 35 U.S.C. 102 above.
Yong further teaches wherein administration of the composition results in a change in a level of a biosafety metric (alanine aminotransferase (ALT)) in the subject that is acceptable compared to baseline (control) (relevant to claims 41, 43, 74, 77), wherein the treatment is safe and well-tolerated (relevant to claim 47). Example 4 of Yong discloses administration of the LNP composition to cynomolgus monkeys via infusion, noting that, “The greater than 30’ infusion time administrations, however, demonstrate lower levels of ALT, a liver injury biomarker.” [00616]-[00618]). Please see also Table 19.
Yong further teaches that administration of the composition reduced TTR levels by at least 95% in the subject (see Example 4, Table 18, Group 4).
Insofar as Yong teaches methods of treating amyloidosis in a subject in need thereof, Yong teaches selecting a subject having ATTR (a monogenic disorder) prior to administration. As a matter of sound scientific reasoning and common sense, to be in need of treatment for a given disorder, a subject must have that disorder (relevant to claims 49 and 50).
Regarding claim 45,Yong teaches that the composition may be administered in an effective amount in the range of 0.01 to 10 mg/kg total RNA content (para [00473], [00616]), which encompasses the claimed dosage range for an average adult human body weight of approximately 65 kg (e.g., 1mg/kg would equal a combine dose of 65 mg).
Yong does not teach the recited biosafety metric outcomes in human subjects, nor the at least 95% reduction in TTR in a human subject as recited in claim 135. Instead, Yong teaches these outcomes in cynomolgus monkeys.
Ding teaches that cynomolgus monkeys are a much better model for human diseases because of their physiological similarities with humans (Abstract). Ding also notes that, “monkeys and human have very similar liver architecture” and that “hepatic arterial fraction and other hemodynamic parameters in monkeys are very close to that in human” (p. 260).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treatment in cynomolgus monkeys, as taught by Yong, to administer the LNP to a human subject instead. The ordinary artisan would have been motivated to do so by Yong’s disclosures that ATTR is a clinically relevant human disease in need of treatment. They would further have had a reasonable expectation that Yong’s efficacy and safety outcomes in non-human primates could have been recapitulated in humans, based on Ding’s teachings that non-human primates, especially cynomolgus monkeys, are a superior model for human diseases because of their physiological similarities, particularly as it pertains to their liver architecture and hemodynamics.
Regarding the claimed dosages, Yong provides a general guideline and range within which to optimize the dose according to subject, body weight, and the efficiency of the particular LNP (including guide RNA) used. Thus in regard to the limitations of the claims, where the prior art teaches a range of possible dosages, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the dosages to determine the most effective dose for the particular subject, LNP formulation, etc. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense to provide routine optimization.
Claims 48, 75-76, and 78 are rejected under 35 U.S.C. 103 as being unpatentable over Yong (cited above) and Ding (cited above), as applied to claims 41, 43, 45-47, 49-50, 74, 77, and 135, further in view of .U.S. PGPUB 20110294868 A1 to Monia (hereinafter ‘Monia’).
Yong and Ding render obvious the methods of claim 41 and/or 43 and/or 46, from which instantly rejected claims 48 depend, as described above.
Yong teaches assessing a biosafety metric compared to baseline after administration (see above), but not prior to.
Yong and Ding also do not teach wherein the biosafety metrics are aPTT, fibrinogen, or AST, as recited in claims 75, 76, or 78.
Monia teaches methods of treating transthyretin amyloidosis, in which the effect of the therapeutic on hepatic function was assessed before and after administration via measurement of plasma concentrations of AST and ALT (para [0496]). Similarly, Monia assessed aPTT and fibrinogen to determine the effect of the therapeutic on coagulation (para [0575]).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method as taught by Yong and Ding to comprise steps of assessing the levels of biosafety markers before and during or after treatment, as taught by Monia, using biosafety metrics appropriate for ATTR, such as aPTT, fibrinogen, and/or AST/ALT, also as taught by Monia. The ordinary artisan would have been motivated to monitor biosafety metrics to assess whether the therapeutic was safe and effective, and would have been motivated to select the above metrics in particular based on Monia’s teachings that they were appropriate for assessing liver function and coagulation in subjects undergoing treatment for ATTR.
Claim 1-4, 6, 42, 44, 49-50 and 135 are rejected under 35 U.S.C. 103 as being as being unpatentable over WIPO Publication 2019/067872 A1 to Kanjolia. (published 04/04/2019; of record, cited on an IDS, hereinafter ‘Kanjolia’).
Regarding claim 1, Kanjolia teaches a method for treating amyloidosis associated with TTR (ATTR) in a subject, comprising administering to the subject a LNP composition comprising an effective amount of:an mRNA encoding a Cas nuclease, and a guide RNA that targets the TTR gene, wherein the administration of the composition reduces serum TTR relative to baseline serum TTR (see claims 3, 13, 14, 106, 66, 75-78).
Kanjolia does not clearly and explicitly teach systemic administration to a human subject, only that the subject is human (see claim 106).
Kanjolia does teach systemic administration of the LNP, via the lateral tail vein, to a well-established humanized transgenic mouse model of hereditary ATTR amyloidosis (para [00282-00284]). Kanjolia further teaches that “This mouse model recapitulates the TTR deposition phenotype in tissues observed in ATTR patients” (Id.). After administration, Kanjolia observed “near complete knockdown of TTR” and “the clearance of TTR protein amyloid deposition in assayed tissues”.
Kanjolia further teaches that ATTR was known to be a clinically significant disease in humans, and that there was an art-recognized need for effective treatments.
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method as taught by Kanjolia to be administered systemically to humans instead of mice. The ordinary artisan would have been motivated by Kanjolia’s teachings that there was an art-recognized need for ATTR treatments in humans. They would also have had a reasonable expectation of success that the treatment would reduce TTR and ATTR symptoms based on the combination of Kanjolia’s teachings that the method was highly effective at reducing TTR and treating symptoms in a mouse model of ATTR, and that the mouse model used was well-known, highly appropriate as a model for the disease, and recapitulates the disease phenotype.
Regarding claims 2 and 3, Kanjolia teaches wherein the ATTR is hereditary transthyretin amyloidosis or wild-type transthyretin amyloidosis (see claims 107, 108)
Regarding claims 4 and 6, Kanjolia teaches wherein the ATTR is hereditary transthyretin amyloidosis with polyneuropathy (see claims 110, 112).
Regarding claims 42 and 44, Kanjolia teaches wherein the administration results in clinical improvement of at least one clinical metric, as described above.
Regarding claims 49 and 50, insofar as Kanjolia teaches methods to subject in needs thereof and that ATTR is a monogenic disorder in humans, Kanjolia teaches selecting a human subject having ATTR prior to treatment.
Regarding claim 135, Kanjolia teaches that at least a 95% reduction of TTr was achieved (see FIG. 24A).
Claims 41, 43, 45-48, and 74-78 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication 2020198697 to Kanjolia (cited above), as applied to claims 1-4, 6, 42, 44 and 135, in view of U.S. PGPUB 20110294868 A1 to Monia (cited above).
Kanjolia renders obvious teaches methods of editing TTR in vivo/treating human subjects with ATTR (a monogenic disorder) comprising administration of a LNP composition comprising a mRNA encoding a Cas nuclease, a guide RNA that targets a gene in the liver (TTR), and editing the gene, as described above.
Kanjolia does not teach wherein the administration results in a change in a level of a biosafety metric in the subject that is acceptable as compared to a baseline level.
Monia teaches methods of treating transthyretin amyloidosis, in which the effect of the therapeutic on hepatic function was assessed before and after administration via measurement of plasma concentrations of AST and ALT (para [0496]). Similarly, Monia assessed aPTT and fibrinogen to determine the effect of the therapeutic on coagulation (para [0575]).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method as taught by Kanjolia to comprise steps of assessing the levels of biosafety markers before and during or after treatment, as taught by Monia, using biosafety metrics appropriate for ATTR, such as aPTT, fibrinogen, and/or AST/ALT, also as taught by Monia. The ordinary artisan would have been motivated to monitor biosafety metrics to assess whether the therapeutic was safe and effective, and would have been motivated to select the above metrics in particular based on Monia’s teachings that they were appropriate for assessing liver function and coagulation in subjects undergoing treatment for ATTR.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
Claims 47 and 48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a human subject having ATTR comprising systemically administering to the human subject a LNP composition comprising an effective amount of an mRNA encoding a Cas nuclease, a guide RNA that targets the TTR gene in the liver, and editing the gene in the liver thereby treating the monogenic disorder, does not reasonably provide enablement for treating the full scope of monogenic disorders and genes encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention
The invention is the class of invention that the CAFC has characterized as “the
unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto
Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Breadth of the Claims
The claims are drawn to a method of treating a generic monogenic disorder targeting any gene in the liver with a CRISPR/Cas system.
Guidance of the Specification
The specification discloses methods of treating ATTR by targeting the TTR gene in the liver, and exemplifies those methods in vivo in clinical trials (see pp. 75-81).
State of the Art
As of 2016, there were approximately 5,000-8,000 known human monogenic disorders (Prakash et al. Current Progress in Therapeutic Gene Editing for Monogenic Diseases. Mol Ther. 2016 Feb 9;24(3):465–474.)(p. 465). The disorders vary widely in the genes, symptoms, and tissues affected. For example, cystic fibrosis is caused by mutations in the CFTR gene and while it primarily involves the lungs it also involves the pancreas, kidney, liver, and GI and reproductive tracts (p. 466). Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and involves muscle tissue (p. 468). Hemoglobinopathies like beta-thalassemia and sickle cell anemia are disorders of the bone marrow (469). One having ordinary skill in the art would not predict, with a reasonable expectation of success, that, for example, using a CRISPR/Cas system to target a gene in the liver would yield a successful treatment for DMD.
Experimentation Required
In order to practice the claimed invention, an undue amount of experimentation would be required. For example, it would be necessary for one of ordinary skill in the art to design and test guide RNAs and test those gRNAs with appropriate Cas enzymes for the full scope of all monogenic disorders. In the case of those monogenic disorders which are not caused by genes expressed in the liver, not only would there be no reasonable expectation of success, but there would be an expectation of failure.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue amount experimentation would be required to make and use the invention as claimed.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMANDA M ZAHORIK/Examiner, Art Unit 1636
Prosecution Insights