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 .
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 42, 45-51 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 methods of treating a liver disease in which a patient expresses a form of PNPLA3 comprising an I148M mutation, does not reasonably provide enablement for treating diseases in patients that do not express a form of PNPLA3 comprising an I148M mutation. 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.
Nature of the Invention and Breadth of the Claims
Claim 42 is drawn to a method of treating, preventing, or ameliorating any disease associated in any way with PNPLA3 by administration of an anionic form of the conjugate comprising the nucleobase sequence of SEQ ID NO: 1089. Claim 45 further limits the disease of claim 42 to liver disease, NAFLD, hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, and primary sclerosing cholangitis. Claims 42 and 45 do not limit the nature of the association of PNPLA3 with the recited disease. The claims embrace methods of treating diseases caused by a loss of PNPLA3 activity through the use of oligonucleotides that would further inhibit any remaining PNPLA3 activity. Claims 47-49 are drawn to treating, preventing or ameliorating of the same diseases.
Claim 50 is drawn to a method of reducing or inhibiting liver damage, steatosis, liver fibrosis, liver inflammation, liver scarring or cirrhosis, liver failure, liver enlargement, elevated transaminases, or hepatic fat accumulation in an individual, comprising administering an anionic form of the conjugate comprising the nucleobase sequence of SEQ ID NO: 1089. Claim 51 further limits the scope of patients to those at risk of any of a list of liver diseases. Claims 50 and 51 do not require any relationship between PNPLA3 and the recited disease.
State of the Art and Level of Predictability in the Art
Bruschi et al (Hepatic Medicine: Evidence and Research, 2017, 9: 55-66, cited from IDS) taught that wild type (native) PNPLA3 encodes for a protein without a fully defined role in liver lipid metabolism. The protein is divergently regulated among distinct liver cell types and different organisms (see Abstract). For example, Bruschi taught that expression in mice and humans differed profoundly. Human PNPLA3 is expressed in a multitude of tissues, but the highest level was found in the liver, followed by retina, skin, adipose tissue, kidney, brain and spleen. Mouse PNPLA3 is more highly expressed in white and brown adipose tissues than liver. Within the liver, murine hepatocytes display higher amount of PNPLA3 compared to hepatic stellate cells (HSCs), whereas human HSCs show more than 2-fold higher expression compared to hepatocytes (see last paragraph of Introduction on page 56). Bruschi taught that the I148M PNPLA3 mutation was highly correlated with a number of liver diseases. For example, I148M correlates with an increased risk for developing hepatic steatosis, nonalcoholic steatohepatitis, advanced fibrosis and cirrhosis; primary sclerosis cholangitis. Patients carrying the I148M genetic variant have reduced survival compared to their WT counterparts; Wilson disease patients showed that the I148M PNPLA3 genotype was significantly associated to increased steatosis prevalence; and I148M has a strong association with hepatocellular carcinoma and non-alcoholic fatty liver disease (see Abstract, and pages 59-63).
Liu et al (US 2017/0349903, December 2017, cited from IDS) taught that there is a strong association between the I148M allele and alcoholic liver disease (ALD), that NAFLD patients and diabetic patients carrying the 148M mutant allele have over 12- and 19-fold higher risk for the development of HCC, respectively, as compared to those who are I148 carriers (See paragraph [0019]. Liu taught that the detailed molecular mechanism underlying the causal role of PNPLA3 I148M in NAFLD/NASH/ALD still remains incompletely understood, however both in vitro cell line studies and in vivo studies using animal models have consistently demonstrated that induction of NAFLD phenotypes requires a dominant-negative effect of PNPLA3 (i.e., overexpression of PNPLA3 148M rather than PNPLA3 148I or gene deletion) (see paragraph [0020]). Liu taught that I148M has been demonstrated as a loss-of-function mutation that reduces the enzymatic activity (triglycerides hydrolase and other unknown function) as compared to the I148 isoform, and that this indicates that I148M plays a pathogenic role in liver disease etiology in a dominant-negative manner (see paragraph [0079]). Due to this dominant negative effect, Liu taught that conventional therapeutic strategies (e.g., to develop agonist or antagonist chemicals targeting the PNPLA3 protein) are unlikely to block the pathogenic effect of PNPLA3 I148M. Instead, Liu emphasized the importance of specifically targeting the PNPLA3 I148M mutation, rather than the wildtype protein (see paragraph [0020]).
In summary, the I148M mutation of PNPLA3 had been correlated with a variety of liver diseases prior to the time if the invention, whereas the wild type form of PNPLA3 had not. Moreover, due to the fact that the I148M mutation is a dominant loss of function mutation, one of skill would not expect that inhibition of any remaining wild type PNPLA3 activity in such individuals would have any positive effect on any PNPLA3-associated disease at the time of the invention.
Guidance and Working examples in the Specification
The instant specification provides no example of the treatment of any disease using the claimed conjugate comprising modified oligonucleotide. The specification provides no guidance as to the effects of inhibiting wild type PNPLA3 in any disease, and provides no disclosure of any disease associated with overexpression of wild type PNPLA3. The specification provides no guidance or examples regarding the treatment of diseases that do not involve PNPL3A (such as those embraced by claims 50 and 51, which recite no nexus to PNPLA3). The specification provides no demonstration that an oligonucleotide comprising instant SEQ ID NO: 1089 can preferentially inhibit I148M PNPLA3 over wild type PNPLA3, nor guidance as to how to achieve such preferential inhibition.
Finding of a Requirement for Undue Experimentation
In view of the breadth of the claims and the nature of the invention (where claims 42, 45-51 do not require expression of a PNPLA3 I148M mutation; claims 45, 49-51 embrace diseases associated with a loss of wild type PNPLA3 function; and where claims 50-51 embrace diseases with no relationship to PNPLA3 at all), the state and predictability of the art (where neither the actual metabolic role of PNPLA3, nor the precise mechanism of the causal role of PNPLA3 I148M in liver diseases was well known, but the role was correlated with a dominant loss of PNPLA3 function; and where those of skill would not expect that inhibition of wild type PNPLA3 would have any positive effect on any PNPLA3-associated disease since those diseases appear to be due to a loss of PNPLA3 function), and the lack of guidance and examples in the specification, one of skill in the art could not practice the invention in commensurate scope with the claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 42, 45-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,774,333. Although the claims at issue are not identical, they are not patentably distinct from each other because claims from ‘333 recite a compound identical to instantly claimed. Further, disclosure of ‘333 recite treatment of the same diseases as in instant invention (see lines 40-65 in column 35) by administration of the compound.
Claims 42, 45-51 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,781,143. Although the claims at issue are not identical, they are not patentably distinct from each other because claims from ‘143 recite a genus of compounds comprising a compound identical to instantly claimed. Further, disclosure of ‘143 recite treatment of the same diseases as in instant invention (see lines 35-65 in column 37) by administration of such compounds.
Claims 42, 45-51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8, 12-17, 23-24, 27-28, 32-33, 40, 42, 45-46, 50-51 of copending Application No. 18/457,955 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because claims from ‘955 recite the methods of treatment of the same diseases as in instant application by administering the same compound comprising the same SEQ ID NO: 1089.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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