Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Application Status
Claims 1-19 are pending and examine on the merits herein.
Claim Rejections - 35 USC § 112(b)
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 1 and 15 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.
Regarding claims 1 and 15, the phrase "optionally" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 112(a)
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 1-19 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 written description rejection.
The teachings of the specification and the claimed invention:
Claims 1-12 are drawn to methods that comprise administration of a genus of compounds recited as “MIC-1 inhibiting agent”. This functionally-defined genus is further recited in claims 2 and 4 to comprise subcategories, which are likewise defined solely by function:
(i) MIC-1 inhibiting agents which decrease the amount of endogenous MIC-1 in said subject;
(ii) MIC-1 inhibiting agents which inhibit the activity of endogenous MIC-1 in said subject;
Dependent claims recite the above subcategories individually or add further functional subcategories such as “catalytic and inhibitory molecules targeted against the MIC-1 gene” (claim 3), “inhibitors of MIC-1 transcription or translation” (claim 3). Structurally, these compounds could be anything. Dependent claims recite structural categories of varying breadth including: anti-MIC-1 antibodies or fragments thereof (claims 3 and 5-6), soluble extra-cytoplasmic receptor domains of MIC-1 receptors (claim 5), soluble molecules or matrix-associated proteins that bind to MIC-1 (claim 5), and peptide mimetic (claim 5) or small organic molecule inhibitors of MIC-1 binding to its receptor (claim 5).
Dependent claims 7-14 recite further limitations for the disease leading to weight loss in the subject, which does not correct the issue identified above for independent claim 1 and therefore these claims are included in this rejection.
Claim 15 is drawn to a method that comprises the administration of a genus of compounds recited as “MIC-1 enhancing agents”.
Claims 16-19 are drawn to a method of preparing a pharmaceutical composition comprising identifying an agent capable of increasing or decreasing the expression level of MIC-1.
The instant specification teaches that such a MIC-1 inhibiting agent may be selected from anti-MIC-1 antibodies or fragments thereof (eg Fab fragments or recombinant scFv fragments (22)), catalytic and inhibitory oligonucleotide molecules targeted against the MIC-1 gene (eg ribozymes, DNAzymes, antisense RNA, and small inhibitory RNA (siRNA)), and inhibitors of MIC-1 transcription or translation; anti-MIC-1 antibodies or fragments thereof (eg Fab fragments or recombinant scFv fragments), soluble extra-cytoplasmic receptor domains of MIC-1 receptors, other soluble molecules or matrix-associated proteins that bind to MIC-1 (eg heparin, heparan sulphate and fetuin), and peptide, peptide mimetic, or small organic molecule inhibitors of, for example, MIC-1 binding to its receptor; peptide, peptide mimetic, or small organic molecule inhibitors might inhibit the activity of endogenous MIC-1 by inhibiting MIC-1 receptor phosphorylation, or transmission of signaling information from the MIC-1 receptor to the cell nucleus, or action of the relevant transcription factor(s) on the cell genome; the MIC-1-inhibiting agent may be an inhibitor of the proconvertase enzyme responsible for cleaving the propeptide from the mature MIC-1 protein domain; but preferably, the MIC-1-inhibiting agent is an anti-MIC-1 antibody or fragment thereof (page 6, line 31- page 7, line 24).
The instant specification discloses that MIC-1 enhancing agents may be selected from MIC-1, and agents which enhance transcription or translation of the MIC-1 gene (eg the p53 transcription factor, which is often seen in elevated levels in diseases associated with MIC-1 over-expression, or agents which enhance p53 expression or activity such as nutlin; and including agents which mimic the activity of MIC-1 (eg active MIC-1 fragments, peptide mimetics of the active domains of MIC-1, and small organic molecules which mimic MIC-1 activity) (page 8, lines 11-21).
The instant specification single species of MIC-1 inhibiting agent, a monoclonal antibody to MIC-1 (MAb26), is reduced to practice. Fetuin is disclosed as a soluble molecule that binds to MIC-1, but this binding is not shown to inhibit MIC-1. No other species of MIC-1 modulating agent is reduced to practice. There are no soluble extra-cytoplasmic receptor domains of MIC-1 receptors, soluble molecules or matrix-associated proteins that bind to MIC-1, peptide mimetics, small organic molecule inhibitors, or functional fragments of MIC-1. Epitope mapping was not done for the single clone.
The instant specification further discloses that fetuin binds to MIC-1 and that it may be an alternative for MIC-1 antibodies (example 8); but there is no evidence that fetuin inhibits MIC-1.
The instant specification further discloses that subclones of the DU145 human prostate carcinoma line transduced with eukaryotic expression vectors containing MIC-1 sequences, and the MIC-1 protein itself, may be considered as species which MIC-1 enhancing agent that are reduced to practice. Of course, tumor cells are not contemplated as agents for administration to modulate appetite, so the MIC-1 protein is the sole described species of MIC-1 enhancing agent. (Examples 4-5).
The instant specification does not define the structural features of the paratope-epitope binding and the residues therein that facilitate binding of an antibody to MIC-1.
The single disclosed species of MIC-1 inhibiting agent is not representative of the indeterminably large claimed genus and it does not establish a clear structure/function correlation could make it possible to predict the structure or partial structure of any additional species. "Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See University of California v. Eli Lilly & Co, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Applicants are directed to the decision in AbbVie Deutsch land GmbH v. Janssen Biotech, Inc. (Fed. Cir. 2014). The court found that if the disclosed species only abide in a corner of the genus, one has not described the genus sufficiently to show that the inventor invented, or had possession of, the genus. He only described a portion of it. In Abbvie, the court stated: "It is undisputed that the structure of the antibody determines its antigen binding characteristic. In order to demonstrate that it has invented what is claimed, AbbVie's patents must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F. 3d at 1568 ("[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material."); Fiers v. Revel, 984 F.2d 1164-1171 , USPQ2d 1601 (Fed. Cir. 1993) ("Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived."). Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus." In the instant case, Applicants have not adequately described representative antibodies to reflect the structural diversity of the claimed genus.
Although applicants may argue that it is possible to screen for MIC-1 enhancing or inhibiting agents as recited in claims 16-19, the court found in (Rochester. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. "As we held in Lilly, "[a]n adequate written description of a DNA ... 'requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention." 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). "For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions."
As detailed below the state of the art does not recognize that a person of ordinary skill in the art could envision a genus of agents defined by function.
The disclosed antibody is not representative of the claimed genus of agents or of just the genus of antibodies therein. This is because when antibodies are raised to an antigen each monoclonal antibody raised comes from one unique cell with unique CDRs which are responsible for antibody binding, such that the structure of CDRs for one antibody cannot be considered representative of other antibodies with different CDRs that bind the same antigen or even substantially the same epitope. Notably, the epitope structure that one antibody binds on an antigen, do not inform the skilled artisan as to what other antibodies would bind the same or substantially the same structure.
Claim analysis:
As detailed below, one skilled in the art would be unable to envision the entire genus of agents that would enhance or inhibit MIC-1.
The state of the art as it applies to the claimed invention:
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Biodrugs (2007), 21 (3): 145-156; page 146, section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence.
Further, it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al. Protein Science (2005), 14:246–248; page 246). 3D structural analyses of antibody-epitope binding highlights the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al. J Comput Chem (2005), 26(9):879-87; page 879).
Ladner (Biotechnology and Genetic Engineering Reviews (2007), 24(1): 1-30) teaches that competitive binding assays demonstrate that two antibodies bind to overlapping or non-overlapping epitopes but not the same epitope (page 3; paragraph 3), so for accurate epitope mapping techniques that can be used are large energy transfer between labeled antibody to an antigen, antigen fragment binding, competitive peptide and antigen binding to antibody, antigen or antibody mutation, antigen-antibody complex analysis by NMR, determination of the 3D crystal structure of the antigen-antibody complex or electron microscopy (pages 5-7).
There are antibodies that bind to MIC-1 known in the art. Moore (The Journal of Clinical Endocrinology & Metabolism, Volume 85, Issue 12, 1 December 2000, Pages 4781–4788; PTO-892) teaches generation of MIC-1 antibodies by immunization of sheep with recombinant human MIC-1, as well as a mouse anti-MIC-1 monoclonal antibody 13C4H3 hybridoma (methods).
Liu (Cancer Res (2003) 63 (16): 5034–5040; IDS entered 05/10/2024) teaches a sheep anti human MIC-1 antibody 233B3 (methods). Liu further teaches that the secretion of MIC-1 in LNCaP cells was modulated by both androgen and estrogen and that modulation of MIC-1 induced different effects in different cell lines (abstract).
Koniaris (Journal of Gastrointestinal Surgery 7, 901–905 (2003); PTO-892) teaches that MIC-1/GDF-15 is induced after administration of nonsteroidal anti-inflammatory drugs (NSAIDS), diallyl disulfides (an antitumor agent found in garlic), and resveratrol (an antitumor agent found in grape skins) (page 902, col 1, para 2).
Bredel (Nat Rev Genet 5, 262–275 (2004); PTO-892) teaches that chemogenomics is the study of genomic and/ or proteomic response of a biological system to chemical compounds (abstract) and further that in reverse chemogenomics gene sequences of interest are expressed as target proteins and screened in a high-throughput target based manner by compound libraries and that on the basis of structure-activity relationship homology concept there is particular emphasis placed on the parallel exploration of gene and protein families (page 263, last para – page 265, 1st para; Fig 1). Bredel further teaches that after hit compounds are identified in the high-throughput assay they are then used in forward chemogenomics to test the lead compounds in biological assays for hit confirmation and off target effects (page 265; Box 2).
Accordingly, one skilled in the art would be unable to predict or envision a genus of agents that enhance or inhibit MIC-1. Since the disclosure fails to describe a sufficient number of species to describe the claimed genus, it is submitted that the written description requirement of 35 U.S.C. 112(a) has not been
Claims 1-14 are rejected under 35 U.S.C. 112, first paragraph, because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. Specifically, the specification is enabling for a method for increasing appetite and/or body weight in a subject suffering from decreased appetite and/or weight loss associated with elevated expression or amounts of MIC-1, said method comprising administering to said subject an effective amount of an anti-MIC-1 antibody or MIC-1-binding fragment thereof. The specification does not reasonably provide enablement for: increasing appetite and/or body weight in healthy subjects or in any condition in an association with elevated MIC-1 has not been established; or methods comprising administration of any other MIC-1 modulating agent.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Colianni, 195 USPQ 150, 153 (CCPA 1977), have been clarified by the Board of Patent Appeals and Interferences in Ex parte Forman, 230 USPQ 546 (BPAI 1986), and are summarized in In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed Cir. 1988). Among the factors are the nature of the invention, the state of the prior art, the predictability or lack thereof in the art, the amount of direction or guidance present, the presence or absence of working examples, the breadth of the claims, and the quantity of experimentation needed. The instant disclosure fails to meet the enablement requirement for the following reasons:
The nature of the invention and the breadth of the claims: All claims 1-14 are directed to methods of increasing appetite and/or body weight. In claims 1-6, the recipient of treatment may be any healthy or diseased subject. Claims 7-14 recite that the subject is suffering from decreased appetite and/or weight loss associated with various conditions: cancer (claims 7, 10, and 11); inflammatory diseases or inflammation (claims 8, 9, and 13); injury, stress (claim 13); radiotherapy or chemotherapy (claim 14). Only claim 12 requires that the condition is associated with a disease, condition, or treatment characterized by MIC-1 over-expression. Only claim 6 recites a specific type of agent for administration, otherwise the administered agent could be anything having the recited functional characteristic of inhibiting the amount or activity of MIC-1. Thus, the enablement of the full breadth of the treatment methods relies on a general correlation between MIC-1 levels and control of appetite in healthy and diseased individuals, and on the administration of as yet unidentified compounds with the required functional characteristics.
The state of the prior art and the predictability or lack thereof in the art: MIC-1 is known to associated with certain cancers such that is a useful marker and a measure of progression in prostatic, breast, colon, and bladder cancers. (US 7,514,221; IDS entered 05/10/2024; column 4, lines 51-67; instant published application at [0004]). A specific role for MIC-1 in controlling appetite has not been suggested in the prior art.
The amount of direction or guidance present and the presence or absence of working examples: Enablement must be provided by the specification unless it is well known in the art. In re Buchner 18 USPQ 2d 1331 (Fed. Cir. 1991). The specification demonstrates that mice bearing a tumor over-expressing MIC-1, either lost weight, or did not gain as much weight as control mice. The weight loss could be reversed by administration with sheep anti-MIC-1 IgG (but not control IgG). This demonstrates that the weight loss in tumor-bearing animals was facilitated by MIC-1. Example 2 also discloses transgenic mice which over express murine MIC-1 under the control of the macrophage specific c-fms promoter. The transgenic mice had elevated MIC-1 levels, decreased appetite and decreased weight. This further supports that MIC-1 suppresses appetite even in the absence of a tumor. It is, therefore, apparent that if an individual is identified as having elevated MIC-1 levels, administration of anti-MIC-1 antibody to said individual would be expected to reverse the weight loss associated with the elevated MIC-1. The specification teaches that MIC-1 expression is normally very low and it rises in response to malignancy, inflammation and injury [0004]. Therefore, there is no reason to expect that further inhibiting MIC-1 below its already low expression would have any significant effect on appetite or body weight in a healthy individual. The specification does not demonstrate any effect of administration of anti-MIC-1 antibody to a healthy individual.
The quantity of experimentation needed: As it is not shown that it is even possible to increase appetite and/or body weight by inhibiting MIC-1 in individuals that have not been shown to express elevated levels of MIC-1, it is not certain that the full range of increasing appetite and/or body weight by inhibiting MIC-1 as required by the instant claims can be achieved regardless of how much experimentation a skilled artisan might be willing to perform.
Furthermore, although the instant closure makes it plausible that methods of increasing appetite and/or body weight by administering agents other than an anti-MIC-1 antibody or MIC-1-binding fragment thereof or MIC-1 will be found, the specification does not enable methods that require administration of agents that have yet to be discovered. As stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to 'inventions' consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the 'inventor' would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis.”
Claim 15 is rejected under 35 U.S.C. 112, first paragraph, because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. Specifically, the specification is enabling for a method for decreasing appetite and/or body weight in a subject suffering from decreased appetite and/or weight loss associated with elevated expression or amounts of MIC-1, said method comprising administering to said subject an effective amount of an anti-MIC-1 antibody or MIC-1-binding fragment thereof. The specification does not reasonably provide enablement for: decreasing appetite and/or body weight in healthy subjects or in any condition has not been established; or methods comprising administration of any other MIC-1 modulating agent.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Colianni, 195 USPQ 150, 153 (CCPA 1977), have been clarified by the Board of Patent Appeals and Interferences in Ex parte Forman, 230 USPQ 546 (BPAI 1986), and are summarized in In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed Cir. 1988). Among the factors are the nature of the invention, the state of the prior art, the predictability or lack thereof in the art, the amount of direction or guidance present, the presence or absence of working examples, the breadth of the claims, and the quantity of experimentation needed. The instant disclosure fails to meet the enablement requirement for the following reasons:
The nature of the invention and the breadth of the claims: Claim 15 is directed to a method of decreasing appetite and/or body weight. Thus, the enablement of the full breadth of the treatment methods relies on the administration of as yet unidentified compounds with the required functional characteristics.
The state of the prior art and the predictability or lack thereof in the art: MIC-1 is known to associated with certain cancers such that is a useful marker and a measure of progression in prostatic, breast, colon, and bladder cancers. (US 7,514,221; IDS entered 05/10/2024; column 4, lines 51-67; instant published application at [0004]). A specific role for MIC-1 in controlling appetite has not been suggested in the prior art.
The amount of direction or guidance present and the presence or absence of working examples: Enablement must be provided by the specification unless it is well known in the art. In re Buchner 18 USPQ 2d 1331 (Fed. Cir. 1991). The specification demonstrates that mice bearing a tumor over-expressing MIC-1, either lost weight, or did not gain as much weight as control mice. The weight loss could be reversed by administration with sheep anti-MIC-1 IgG (but not control IgG). This demonstrates that the weight loss in tumor-bearing animals was facilitated by MIC-1. Example 2 also discloses transgenic mice which over express murine MIC-1 under the control of the macrophage specific c-fms promoter. The transgenic mice had elevated MIC-1 levels, decreased appetite and decreased weight. This further supports that MIC-1 suppresses appetite even in the absence of a tumor. It is, therefore, apparent that if an individual is identified as having elevated MIC-1 levels, administration of anti-MIC-1 antibody to said individual would be expected to reverse the weight loss associated with the elevated MIC-1. The specification teaches that MIC-1 expression is normally very low and it rises in response to malignancy, inflammation and injury [0004]. Therefore, there is no reason to expect that further inhibiting MIC-1 below its already low expression would have any significant effect on appetite or body weight in a healthy individual. The specification does not demonstrate any effect of administration of anti-MIC-1 antibody to a healthy individual.
The quantity of experimentation needed: As it is not shown that it is even possible to decrease appetite and/or body weight by enhancing MIC-1 in individuals, it is not certain that the full range of decreasing appetite and/or body weight by inhibiting MIC-1 as required by the instant claims can be achieved regardless of how much experimentation a skilled artisan might be willing to perform.
Furthermore, although the instant closure makes it plausible that methods of decreasing appetite and/or body weight by administering agents other than recombinant MIC-1, the specification does not enable methods that require administration of agents that have yet to be discovered. As stated in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), “If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to 'inventions' consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the 'inventor' would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis.”
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 1-7 and 15-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 8,192,735 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1, 3, and 5, the patented claims teach a method for increasing appetite and/or body weight in a subject suffering from decreased appetite and/or body weight loss associated with elevated expression or amounts of MIC-1, said method comprising administering to said subject an effective amount of an anti-MIC-1 antibody or MIC-1 binding fragment thereof optionally in admixture with a pharmacologically-acceptable carrier and/or excipient (claim 1),
Regarding claim 2, the patented claims teach wherein said anti-MIC-1 antibody or MIC-1 binding fragment thereof decreases the amount of endogenous MIC-1 in said subject (claim 2).
Regarding claim 4, the patented claims teach wherein said anti-MIC-1 antibody or MIC-1 binding fragment thereof inhibits the activity of endogenous MIC-1 in said subject (claim 3).
Regarding claim 6, the patented claims teach wherein said anti-MIC-1 antibody is a humanized monoclonal anti-MIC-1 antibody (claim 4).
Regarding claim 7, the patented claims teach wherein the subject is suffering from decreased appetite and/or weight loss associated with advanced cancer (claim 5).
Regarding claim 15, the patented claims teach a method for decreasing appetite and/or body weight in a subject, said method comprising administering to said subject an effective amount of MIC-1, optionally in admixture with a pharmacologically-acceptable carrier and/or excipient (claims 6-7).
Regarding claims 16-19, the patented claims teach a method for assessing the effect of an agent on the appetite and/or body weight of a subject, said method comprising administering said agent to said subject and detecting any increase or decrease in the amount of MIC-1 in said subject, wherein an increase in the amount of MIC-1 indicates that said agent decreases appetite and/or body weight in a subject and a decrease in the amount of MIC-1 indicates that said agent increases appetite and/or body weight in a subject (claim 8).
Claims 8-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 8,192,735 B2 as applied to claims 1-7 and 15-19 above and further in view of Walsmith (Int J of Cardiology, 2002, 85(1): 89-99; PTO-892) and
The teachings of the patented claims regarding 1-7 and 15-19 are detailed above.
The patented claims do not teach wherein the subject is suffering weight loss associated with rheumatoid arthritis.
Walsmith teaches that rheumatoid arthritis is a debilitating, chronic, systemic, autoimmune disease that is accompanied by a loss of body cell mass (abstract). Walsmith further teaches that weight loss was not caused by anorexia alone, but that chronic inflammation was an important mediator of weight loss in a rat adjuvant arthritis model (page 93, col 2, first para).
Moore teaches that macrophages are important mediators in orchestrating chronic inflammatory and fibrotic disorders, such as atherosclerosis and rheumatoid arthritis (page 4, last para). Moore further teaches that MIC-1 expression is activation related in macrophages (page 5, 2nd para) but also possesses immunomodulatory activity (page 5, 4th para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to treat weight loss caused by rheumatoid arthritis as taught by Walsmith with increased MIC-1 expression as taught by Moore with a method of increasing appetite by administering a MIC-1 antibody as taught by the patented claims. The ordinary artisan would have been motivated to do so because Moore teaches that MIC-1 is expressed on activated macrophages and that macrophages are important mediators in orchestrating chronic inflammatory disorders including rheumatoid arthritis and Walsmith teaches that rheumatoid arthritis is a debilitating, chronic, systemic, autoimmune disease that is accompanied by a loss of body cell mass that was not caused by anorexia alone, but mediated by chronic inflammation. The ordinary artisan has a reasonable expectation of success to apply the method of increasing appetite by administering a MIC-1 antibody to a patient suffering from decreased appetite caused by rheumatoid arthritis with increased expression of MIC-1.
Claims 10-12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 8,192,735 B2 as applied to claims 1-7 and 15-19 above and further in view of Koopman (Clin Cancer Res (2004) 10 (7): 2386–2392; PTO-892).
The teachings of the patented claims regarding 1-7 and 15-19 are detailed above.
The patented claims do not teach wherein the subject is suffering from pancreatic cancer.
Koopman teaches that patients with pancreatic ductal adenocarcinoma usually present with advanced-stage disease and a dismal prognosis and that MIC-1 is expressed at higher levels in pancreatic cancer than non-neoplastic pancreatic tissue (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to treat a subject suffering from pancreatic cancer that overexpresses MIC-1 as taught by Koopman a method of increasing appetite by administering a MIC-1 antibody as taught by the patented claims. The ordinary artisan would have been motivated to do so because Koopman teaches that patients with pancreatic ductal adenocarcinoma usually present with advanced-stage disease and a dismal prognosis and that MIC-1 is expressed at higher levels in pancreatic cancer than non-neoplastic pancreatic tissue as the patented claims are already directed at treatment of appetite in advanced cancer. The ordinary artisan has a reasonable expectation of success to apply the method of increasing appetite by administering a MIC-1 antibody to a patient suffering from decreased appetite caused by advanced pancreatic cancer with increased expression of MIC-1.
Claims 12-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 8,192,735 B2 as applied to claims 1-7 and 15-19 above and further in view of Koniaris (Journal of Gastrointestinal Surgery 7, 901–905 (2003); PTO-892) and Padillo (Nutrition, 2002, 18: 987-90; PTO-892).
The teachings of the patented claims regarding 1-7 and 15-19 are detailed above.
The patented claims do not teach wherein the subject is suffering from decreased appetite or weight loss associated with MIC-1 over expression; or wherein the subject is suffering from injury inflammation.
Koniaris teaches that MIC-1 expression is rapidly induced after a wide variety of murine acute and chronic liver injuries (abstract). Koniaris further teaches that MIC-1/GDF-15 functions are under active investigation and currently appear to fall into two broad categories: growth control and inflammation and further that MIC-1/GDF-15 has been identified as a p53-inducible gene and has been implicated in growth inhibition following p53 activation (page 902, col 1, para 2). Koniaris further teaches that MIC-1/GDF-15 is induced after administration of nonsteroidal anti-inflammatory drugs (NSAIDS), diallyl disulfides (an antitumor agent found in garlic), and resveratrol (an antitumor agent found in grape skins) (page 902, col 1, para 2).
Padillo teaches that anorexia and malnutrition seem to be related to the intensity of biliary obstruction, liver injury, and anorectic endocrine mediators such as CCK and leptin (conclusion). Padillo teaches that the improvement of oral intake and nutrition state of patients with obstructive jaundice after biliary drainage may be linked to increased appetite as spontaneous food intake improves significantly after biliary drainage in patients with benign or malignant obstruction. However, more than 50% of patients with cancer maintained food intakes below the estimated calorie requirements 1 wk after internal biliary drainage (pages 988-989).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to treat anorexia caused by liver injury as taught by Padillo with increased MIC-1 expression as taught by Koniaris with a method of increasing appetite by administering a MIC-1 antibody as taught by the patented claims. The ordinary artisan would have been motivated to do so because Koniaris teaches that MIC-1 expression is rapidly induced after a wide variety of acute and chronic liver injuries and Padillo teaches that anorexia and malnutrition seem to be related to the intensity of biliary obstruction and/ or liver injury which cannot be relieved by biliary drainage in some patients. The ordinary artisan has a reasonable expectation of success to apply the method of increasing appetite by administering a MIC-1 antibody to a patient suffering from decreased appetite caused by liver injury with increased expression of MIC-1.
Claims 14 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 8,192,735 B2 as applied to claims 1-7 and 15-19 above and further in view of Tisdale (Nutrition, 2001, 17(5): 438-442; PTO-892).
The teachings of the patented claims regarding 1-7 and 15-19 are detailed above.
The patented claims do not teach wherein the subject is suffering from weight loss due to chemotherapy.
Tisdale teaches that treatment of cancer, particularly with chemotherapy, causes nausea and vomiting, leading to anorexia and weight loss. Tisdale further teaches that weight loss due to anorexia caused by chemotherapy should be distinguished from cancer cachexia and will require different therapeutic interventions (intro, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to treat anorexia caused by chemotherapy as taught by Tisdale with a method of increasing appetite by administering a MIC-1 antibody as taught by the patented claims. The ordinary artisan would have been motivated to do so because Tisdale teaches that treatment with chemotherapy causes nausea and vomiting leads to anorexia and weight loss that necessitates a different therapeutic intervention versus cachexia induced by cancer. The ordinary artisan has a reasonable expectation of success to apply the method of increasing appetite by administering a MIC-1 antibody to a patient suffering from decreased appetite caused by chemotherapy.
Claim 15 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,946,146 B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claim 15, the patented claims teach a method for decreasing appetite and/or body weight in a subject, said method comprising administering to said subject an effective amount of an active MIC-1 fragment optionally in admixture with a pharmacologically-acceptable carrier and/or excipient (claim 1).
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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