DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/17/2025 has been entered.
Notice of Pre-AIA or AIA Status
2. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
3. Applicant’s amendments and remarked, filed 02/18/2026, are acknowledged. Claims 3, 5, 26, 27, 31 and 34 are amended. Claims 3, 5, 22-32, 34, and 35 are pending. As such, claims 3, 5, 22-32, 34, and 35 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted 12/06/2024 and 11/13/2023 are acknowledged and the references therein are considered, unless indicated otherwise.
Information Disclosure Statement
5. The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
Specification
6. The use of the terms Nexavar, Novartis, Tafinlar, and Zelboraf (page 18) , which are a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Withdrawn Rejections
7. The following rejections are withdrawn:
a. The rejections of claims 5 and 7 under 35 U.S.C 112(b) for being indefinite for
failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention as set forth at pp. 18-19 of the previous Office action (mailed 19 August 2025) is withdrawn in view of the amended claims submitted with the remarks filed 02/18/2026.
b. The rejection of claims 3, 5, and 22-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 8, 9, 11, 14, 18, 21, 23, 26, 27, 29, 31, 34, 38, 41, 43, and 46-48 of copending Application No. 18/999,018 as set forth at p. 15 of the previous Office action (mailed 19 August 2025) is withdrawn in view of the amended claims in the instant application and applicants argument is found persuasive with the remarks filed 02/18/2026.
c. The rejection of claims 3, 5, and 22-32 on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of US 10,865,240 B2 as set forth at p. 16 of the previous Office action (mailed 19 August 2025) is withdrawn in view of the amended claims in the instant application and applicants argument is found persuasive with the remarked filed 02/18/2026.
d. The rejection of claim(s) 3, 5, and 22-30 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Cook et al. (US 2017/0174759 A1; published 22 June 2017, effectively filed 16 December 2015)as set forth at pp. 19-20 of the previous Office action (mailed 19 August 2025) is withdrawn as applicant’s arguments are found persuasive in the remarks filed 02/18/2026.
Maintained Rejections
Claim Rejections - 35 USC § 103
8. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3, 5, and 22-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Edwards et al. (US 2014/0219919 A1; published 07 August 2014) in view of WO 2018/109174 (SINGAPORE HEALTH SERVICES PTE & NATIONAL UNIVERSITY OF SINGAPORE; published 21 June 2018; hereinafter ‘174).
This rejection is maintained for reasons of record (pp. 12-13, Office action mailed 19 August 2025) and for the reasons discussed below. For convenience, the rejection is repeated herein, modified slightly to address the amended claims’ limitations:
Edwards et al. teach a method of treating or preventing a metabolic disease, comprising administering a therapeutically or prophylactically effective amount of an agent capable of inhibiting IL-11-mediated signaling by preventing or reducing the binding of IL-11 to IL-11Rα to a subject, wherein the metabolic disease can be cachexia. See [0010], [0013], [0159], [0160]-[0163]. The agent preferred by Edwards et al. is an antagonistic IL-11Rα antibody.
Edwards et al. do not teach an antagonistic IL-11 antibody, or selecting patients in whom IL-11 expression is upregulated.
‘174 teaches methods of treatment comprising administering to a subject an antagonistic IL-11 antibody, wherein the disease is one that is mediated by IL-11 signaling and comprises diabetes, such as diabetic retinopathy and diabetic nephropathy. See abstract; p. 22 li. 20-23 and 29-32; p. 46 li. 22 – p. 47 li. 17; pp. 57-63. ‘174 further teaches selection of a subject by testing for IL-11 upregulation. See p. 23 li.1-4; pp. 57-63.
Therefore, it would have been obvious to one of ordinary skill in the art at the time the application was filed to modify the method of treating/preventing a metabolic disease such as cachexia, comprising administering a therapeutically or prophylactically effective amount of an agent capable of inhibiting IL-11-mediated signaling by preventing or reducing the binding of IL-11 to IL-11Rα to a subject (as taught by Edwards et al.) by using the preferred IL-11 inhibiting antibody of ‘174 as the IL-11 inhibiting agent. There would have been a reasonable expectation of success, given the teachings of Edwards et al. that inhibition of IL-11 signaling is effective for treating these diseases, and ‘174’s teaching that their IL-11 antagonistic antibody inhibits IL-11 signaling. The motivation to do so would have been the recognition by the ordinary skilled artisan that the IL-11Rα antibody of Edwards et al. and the IL-11 antibody of ‘174 are functional equivalents insofar as they both inhibit IL-11-mediated signaling and both are useful for treating diseases mediated by IL-11 signaling.
As noted by the United States Supreme Court, if a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability. KSR, 127 S. Ct. at 1740. "When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product is not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show it was obvious under 35 U.S.C. 103." KSR Int'l Co. v. Teleflex Inc., 127 S.Ct. 1727, 1742, 82USPQ2d 1385, 1396 (2007).
Applicant’s Arguments
Applicant’s arguments (pp. 10-11, remarks received 18 February 2026) have been fully considered but are not found to be persuasive for the following reasons.
Applicant argue that the ‘174 application does not fully address the use of anti-IL-11 antagonists for treating diabetes and disagrees that diabetic retinopathy and diabetic nephropathy are types of diabetes. Applicant argues that diabetic nephropathy is a subtype of a chronic kidney disease and diabetic retinopathy is a subtype of retinopathy. Applicant argues the amended claims that no longer recite cachexia, washing, cachexia, chemotherapy-associated weight loss, pre-cachexia, refractory cachexia, sarcopenia, anorexia or myopenia and the amended claims are not prima facie obvious over the ‘919 applicant and the ‘174 applicant.
Response to Arguments
This has been fully considered but is not found to be persuasive. This has been fully considered but is not found to be persuasive. MPEP 2123 [R-5] teaches that patents are relevant as prior art for all they contain. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). In the instant case, application ‘174 clearly states the antibodies/fragments of the present invention can be used to treat type 1 diabetes mellitus (pages 64, line 29). There is no reason to doubt that application ‘174 does not suggest a subtype of diabetes. Accordingly, the combination of references provides the use of anti-IL-11 antagonist to treat diabetes.
Double Patenting
9. 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
US 11,813,311 B2:
Claims 3, 5, and 22-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US 11,813,311 B2. Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons set forth at p. 24 of the previous Office action (mailed 07 February 2025) and for the following reasons.
This rejection is maintained for reasons of record (pp. 8-14, Office action mailed 07 February 2025) and for the reasons discussed below. For convenience, the rejection is repeated herein:
Both sets of claims recite methods of administering IL-11-mediated signaling inhibitors, including anti-IL-11 antibody products, for the treatment of metabolic disease. The claims differ in the precise diseases being treated. However, the patented claims recite diseases associated with, or comprising, diabetes, such as insulin-resistance. Therefore, the patented claims reasonably suggest the instantly claimed patient populations. Regarding the ‘311 patent, Applicant requests that the rejection be held in abeyance until allowable subject matter is identified. This has been fully considered but is not found to be persuasive. Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), which states:
A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional.
As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Replies with an omission should be treated as provided in MPEP § 714.03.Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner. See MPEP § 804.02, subsection VI, for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995. (emphasis added)
Accordingly, the rejection is maintained and is expressly not held in abeyance.
Applicant’s Arguments
Applicant argues that the rejected claims depend directly or indirectly from the amended claims and will consider filing a Terminal Disclaimer to overcome this rejection should it remain after consideration.
Response to Arguments
This has been fully considered but is not found to be persuasive. Both sets recite methods of administering IL-11-mediated signaling inhibitors, including anti-IL-11 antibody products, for the treatment of metabolic disease.
The claims differ in the precise diseases being treated. However, the patented claims recite diseases associated with, or comprising, diabetes, such as insulin-resistance. Therefore, the patented claims reasonably suggest the instantly claimed patient populations. The patent claims also recite a pancreatic injury such as pancreatitis
Applicant’s request that the rejection be held in abeyance until allowable subject matter is identified. This has been fully considered but is not found to be persuasive. Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), as stated above from the previous rejection. Accordingly, the rejection is maintained and is expressly not held in abeyance.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
10. Claim 3 is rejected under 35 U.S.C. 112(b) as being indefinite. The phrase “is, or comprises” when used to define a disease condition lacks reasonable certainty as to its scope. “Comprises” is a transitional term of art applicable to claim elements or steps, and its applicant to a disease state, i.e., that a subjects metabolic disease “comprises” type 2 diabetes, has not clear meaning to one of ordinary skill in the art. A disease is not a collection of components that can be “comprised”. It is a medical condition that a subject either has or does not have. It is unclear what disease states would or would not satisfy this limitation.
Rejections under 112(a)
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.
Enablement
11. Claims 3, 5, 22-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signaling. 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.
Case law holds that applicant' s specification must be “commensurately enabling [regarding the scope of the claims]” Ex Parte Kung, 17 USPQ2d 1545, 1547 (Bd. Pat. App. Inter. 1990). Otherwise undue experimentation would be involved in determining how to practice and use applicant' s invention. The test for undue experimentation as to whether or not [Claimed Feature] within the scope of the claims can be used [meet the claim requirements] as claimed and whether the claims meet the test is stated in Ex parte Forman, 230 USPQ 546, 547 Application/Control Number: 18/128,310 Page 5 Art Unit: 1674 (Bd. Pat. App. Inter. 1986) and In re Wands, 8 USPQ2d 1400, 1404 (Fed.Cir. 1988). Upon applying this test to claim 17, it is believed that undue experimentation would be required because: (A) Nature of the invention, (B) State of the prior art, (C) The level of one of ordinary skill, (D) The level of predictability in the art, (E) Amount of direction provided, (F) The existence of working examples,(G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
(1) Nature of the invention and (6) Breadth of the claims
The claims broadly encompass a genus of antibodies that comprise anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signaling. The claims state that a method of treating a metabolic disease, comprising administering a therapeutically effective amount of an anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signalling to a subject, wherein the metabolic disease is, or comprises, type 2 diabetes (T2D), type 1 diabetes (T1D), non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver (NAFL), lipodystrophy, lipohypertrophy, lipoatrophy, diabetes or pancreas injury. The specification an agent capable of inhibiting interleukin 11 (IL-11)-mediated signaling for use in a method of treating or preventing a metabolic disease. Also provided is the use of an agent capable of inhibiting interleukin 11 (IL-11)-mediated signaling in the manufacture of a medicament for use in a method of treating or preventing a metabolic disease (page 4). The specification teaches the agent is selected from the group consisting of: an antibody or an antigen- binding fragment thereof, a polypeptide, a peptide, a nucleic acid, an oligonucleotide, an aptamer or a small molecule (page 4).
Thus, the claims are broad in that they encompass a vast genus of antibodies or antigen-binding fragment thereof comprising fewer than all six CDRs and in any combination, and having specific functional requirements, including treating a metabolic disease such as type 2 diabetes (T2D), type 1 diabetes (T1D), non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver (NAFL), lipodystrophy, lipohypertrophy, lipoatrophy, diabetes or pancreas injury (5) The state of the prior art and (7) The predictability or unpredictability of the art
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. Paul (Fundamental Immunology, 3rd Edition, Raven Press, New York, Chapter 8, pages 292-295, 1993) teaches that the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (See pages 293-295). While some publications acknowledge that CDR3 is important for antigen binding, the conformations of other CDRs as well as the framework are equally important in antigen binding. For example, MacCallum et al. (Journal of Molecular Biology, 262:732-745, 1996) analyzed antigen-contacting residues and combining site shape of various antibodies and state that although CDR3 of the heavy chain and light chain dominate, a number of residues outside of the standard CDR definitions make antigen contacts (See page 733) . MacCallum et al. teach that antigens tend to bind to the antibody residues located at the center of the combining site where the six CDRs meet (See abstract and page 742) and less central CDR residues are only contacted by large antigens (See page 733 and 735). MacCallum et al. further teach that non-contacting residues are important in defining "canonical" backbone conformations.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is further underscored by Casset et al. (Biochemical and Biophysical Research Communications, 307:198-205, 2003), which discuss the importance of multiple CDRs in antigen contact. Casset et al. teach that all antibodies have six CDR residues, all of which are more or less involved in antigen recognition (See page 199). Casset et al. teach that peptide mimetics of antibody combining sites have previously only targeted CDR H3, since this CDR is typically at the center of most, if not all, antigen interactions; however this strategy is flawed since other CDRs play an important role in the recognition of antigen (See page 199). Casset et al. construct a peptide mimetic of an anti-CD4 monoclonal antibody, containing antigen contact residues from five CDR regions, except L2 and additionally using a framework residue located just before the H3 and show that the peptide has high binding to CD4, thus signifying the contribution of multiple CDRs, and not a single CDR, in antigen recognition (See page 202 and Figure 4). Vajdos et al. (Journal of Molecular Biology, 2002 Jul 5;320(2):415-28) additionally states that, “ ... Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.
Further, Sela-Culang et al. 2013 (The structural basis of antibody-antigen recognition; Frontiers in Immunology 4(302):1-13) teach the hypervariable loops within the variable domains of antibody polypeptides are widely assumed to be responsible for antigen recognition while the constant domains are believed to mediate effector activation, but that recent analysis indicates that their clear functional separation between the two regions is an over-simplification (see abstract). Sela-Culang et al. teach some residues within the CDRs may not participate in antigen binding and some residues outside the CDRs (e.g. in framework regions and in the constant domains) often contribute critically to the integration with the antigen (see abstract). Sela-Culang et al. teach understanding the role of each structural element is essential for successful engineering of binding polypeptides (e.g. page 2, left column). Sela-Culang et al. teach almost all of the residues predicted to be part of an epitope may be considered as correct predictors as they will bind to some antibodies but also are false predictors as they don’t bind to the others and accordingly that predicting that a residue is not in an epitope may be either a true negative or a false negative depending on the anybody considered (page 2, right column). Sela-Culang et al. teach each CDR has its own unique amino-acid composition different from the composition of the other CDRs and that each CDR has a unique set of contact preferences favoring certain amino acids over others (page 5-6, bridging). Sela-Culang et al. teach the combined action of all six CDRs is the evolutionary response of the immune system that enables the antibody polypeptide to recognize virtually any surface patch on the antigen (page 6). Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the antibody per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
(6) The amount of direction or guidance by the inventor; (7) The existence of working examples
Although the specification discloses an agent capable of inhibiting interleukin 11 (IL-11)-mediated signaling for use in a method of treating or preventing a metabolic disease. Also provided is the use of an agent capable of inhibiting interleukin 11 (IL-11)-mediated signaling in the manufacture of a medicament for use in a method of treating or preventing a metabolic disease (page 4), the agent is selected from the group consisting of: an antibody or an antigen- binding fragment thereof, a polypeptide, a peptide, a nucleic acid, an oligonucleotide, an aptamer or a small molecule (page 4), the specification does not recite all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, which are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect IL-11 antibodies having the claimed functions, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the genus of IL-11 antibody defined by a partial structure and their function only in a method of treating a metabolic disease. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including treating a metabolic disease with the administration of anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signaling. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, the changes which can be made in the protein's structure and still maintain activity is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Exparte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
New Grounds of Rejection
Written Description
The following rejection is a written description rejection. This written description has two issues. One issue is written description with regard to incomplete antibody due to missing CDRs and the other issue is regarding lack of structure for an antibody.
12. Firstly, claims 31 and 34 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.
Claims 31 and 34 recite administration of specific IL-11 antibodies, or an antigen-binding fragment thereof, which comprises six specific CDR sequences, or a variant thereof in which one amino acid in one or both of HC-CDR2 and LC-CDR2 is substituted with another amino acid. Therefore, both of the claims read on methods of using antibody products that comprise less than the full complement of six CDR sequences comprising the amino acid sequences of (1) SEQ ID NOs: 40-45 (corresponding to antibody “Enx203”) or (2) SEQ ID NOs: 34-39 (antibody “Enx108A”). The claims recite a genus of antibody products having (1) an explicitly recited functional feature of specifically binding any IL-11 protein; (2) an explicit function of being an antagonist of IL-11-mediated signaling; and (3) an implied functional feature of having an activity to be therapeutically effective in the therapeutic method of treating a metabolic disease. However, the claims recite only partial structural features.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
Regarding structure-function correlation, it is noted that one of skill in the art was aware that there is a lack of structure-function correlation in antibody molecules. Evidence of such in the form of publications in the art include the following.
First, the prior art recognizes that the full six CDR sequences are required to form the part of an antibody, i.e., the paratope, that specifically binds the target antigen. See Al Qaraghuli et al. (2020, Nature Scientific Reports 10:13969), who state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen.
However, the prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (2003, JMB 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
Lloyd et al. (2009, Protein Engineering, Eng. Design & Selection 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Goel et al. (2004, J. Immunol. 173: 7358-7367) teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues. (See entire reference).
Khan et al. (2014, J. Immunol. 192: 5398-5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity...Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naive BCR repertoire, because Kaji et al... .have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Poosarla et al. (2017, Biotechn. Bioeng. 114(6): 1331 -1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Rabia, et al. (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al. report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Rabia et al. thus teach that affinity and specificity are not necessarily correlated and that and increase in affinity does not indicate an increase in specificity (Fig. 3; p. 368, col. 1, section 3,1st full paragraph to col. 2, 2nd full paragraph).
Conversely, evidence also shows that some functionally diverse antibodies can share some structural similarities, including an entire CDR region. See Igawa et al. (US 9,334,331 B2), who disclose antibody Q153 that binds human Factor IXa. Q153 comprises a VH-CDR1 identical to the VH-CDR1 of antibody 11E12 disclosed by Gonzales et al. (US 10,421,807 B2). However, 11E12 specifically binds canine IL-31, a protein having no structural or functional similarity to human Factor IXa. This illustrates that even when some CDR regions share 100% structural identity, the antibodies in which they are comprised can have completely different functions (i.e., binding specificities).
The combination of evidentiary publications thus underscores a lack of structure-function correlation in antibody molecules.
Regarding a representative number of species, the instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. While the specification provides general descriptions of how to make variant antibodies that bind IL-11 proteins and how to test them for desired binding and therapeutic activities, only one species of Enx203 antibody and one species of Enx108A antibody within the claimed Enx203-based and Enx108A-based genera are described with sufficient identifying characteristics using precise definitions such as structure, formula, chemical name, or physical properties such that one skilled in the art could visualize or recognize the identity of the claimed subject matter. Such is not representative of the claimed genera. While the larger genus of antagonistic IL-11 antibodies recited in claims 3, 5, and 23-25 are supported by the prior art disclosures of many such IL-11 antagonistic antibodies, none of these prior art antibodies fall within the subgenera claimed, i.e., Enx203-based antibodies and Enx108A-based antibodies, and thus cannot be relied upon as additional species supporting the subgenera.
Applicant’s attention is directed to the recent decision in Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The court discussed whether an antibody is adequately described by describing a newly characterized antigen. Specifically, the court referred to the decision in Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011). In that case, the patentee claimed a genus of antibodies containing a human variable region that has particularly desirable therapeutic properties: high affinity, neutralizing activity, and A2 specificity. Despite the fact that the specification disclosed human TNF-α protein, and despite the disclosure of the structures of more than one species of antibody related to the genus, the court ruled that that the generic antibody claims at issue were invalid for lack of written description. The fact pattern is similar in the instant case. As in the court case, the instant claims recite a genus of antibodies that have affinity for a specific antigen and have a desirable special property, i.e., ability to be therapeutically effective in methods of treating tumors or inducing an immune response. Following the finding in Centocor, the instant claims are found to lack adequate written description. Similarly, in Juno Therapeutics, Inc., Sloan Kettering Institute for Cancer Research v. Kite Pharma, Inc. (Case 2020-1758, CAFC August 2021), the court found that the disclosure of two antibody products (scFv molecules) was insufficient to support written description for the claimed genera, specifying that the specification at issue failed to disclose “structural features common to the members of the genus to support that the inventors possessed the claimed invention;” i.e., the specification and evidence of record failed to provide a structure-function correlation. In the instant case, there is also no evidence of a structure-function correlation for antibodies, and thus the claims are properly rejected for lack of adequate written description.
Secondly, Claims 3, 5, 22-25 are drawn to a method of treating a metabolic disease, comprising administering a therapeutically effective amount of an anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signalling to a subject, wherein the metabolic disease is, or comprises, type 2 diabetes (T2D), type 1 diabetes (T1D), non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver (NAFL), lipodystrophy, lipohypertrophy, or lipoatrophy; wherein the anti-IL-11 antibody or an antigen binding fragment thereof prevent or reduce; wherein the interleukin 11 receptor is or comprises IL-IIRa; wherein the method comprises administering the agent to a subject in which expression of interleukin 11(IL-11) or a receptor for IL-11 (IL-IIR) is upregulated; wherein the method comprises administering the agent to a subject in which expression of IL-11 or an IL-1IR has been determined to be upregulated; wherein the method comprises determining whether expression of IL-11 or an IL-11R is upregulated in the subject and administering the agent to a subject in which expression of interleukin 11 IL-11 or an IL-11R is upregulated.
Claims 26-30 are drawn a method of treating a metabolic disease, comprising administering a therapeutically effective amount of an anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signaling to a subject; wherein the metabolic disease is, or comprises: diabetes or pancreas injury; wherein the anti-IL-11 antibody or an antigen binding fragment thereof prevent or reduce the binding of interleukin 11 (IL-11) to a receptor for interleukin 11 (IL-11R); wherein the method comprises administering the agent to a subject in which expression of IL-11 or an IL-1IR is upregulated; wherein the method comprises administering the agent to a subject in which expression of IL-11 or an IL-1IR has been determined to be upregulated; wherein the method comprises determining whether expression of IL-11 or an IL-11R is upregulated in the subject and administering the agent to a subject in which expression of IL-11 or an IL-1IR is upregulated.
The specification teaches an agent capable of inhibiting interleukin 11 (IL-11)-mediated signaling for use in a method of treating or preventing a metabolic disease. Also provided is the use of an agent capable of inhibiting interleukin 11 (IL-11)-mediated signaling in the manufacture of a medicament for use in a method of treating or preventing a metabolic disease (page 4). The specification teaches the agent is selected from the group consisting of: an antibody or an antigen- binding fragment thereof, a polypeptide, a peptide, a nucleic acid, an oligonucleotide, an aptamer or a small molecule (page 4).
The claims state that the anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signaling to a subject to treat a metabolic disease. However, the specification provides no guidance regarding any antibody or antigen-binding fragment thereof that specifically binds IL-11 and does not define all six complementary domain regions (CDRs). The specification does not provide adequate written description to identify the broad genus of the claims because the specification does not disclose a correlation between the necessary structure of the antibody, and the claimed functions to be maintained (i.e. administering anti-IL-11 antibody to treat metabolic disease). Thus, the specification does not distinguish the claimed genus from others, except by function. Although the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by members of the genus because, while the description of an ability of a claimed antibody or antibody fragment thereof may generically describe that molecule’s function, it does not describe the molecule itself. A definition by function does not suffice to define the genus because it is only an indication of what the antibody or antigen-binding fragment thereof does, rather than what it is; therefore it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of antibodies, is highly variable (i.e. each different antibody capable of binding to IL-11 would necessarily have a unique sequence of amino acids; see MPEP 2434), the functional characteristic of binding to something specific, is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies or antigen-binding fragments thereof claimed only by a partial structure and functional characteristics.
Additionally, the specification fails to disclose a representative number of species. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g. see In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]; emphasis added. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claims, claimed only by a partial structure and functional characteristics and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous antibodies had not yet been identified and thus the specification represents little more than a wish for possession; See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516,1521,222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming a rejection for lack of written description because the specification does "little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of antibodies claimed only by a partial structure and functional characteristics.
In Abbvie v. Centocor (Fed. Cir. 2014), the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that 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. The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus to a method of treating a metabolic disease, comprising administering a therapeutically effective amount of an anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signalling to a subject, wherein the metabolic disease is, or comprises, type 2 diabetes (T2D), type 1 diabetes (T1D), non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver (NAFL), lipodystrophy, lipohypertrophy, lipoatrophy, diabetes or pancreas injury. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signaling comprising fewer than six CDRs do not meet the requirements under 35 U.S.C. 112 first paragraph because the skilled artisan cannot envision the detailed chemical structure of the encompassed antibody variants, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. Paul (Fundamental Immunology, 3rd Edition, Raven Press, New York, Chapter 8, pages 292-295, 1993) teaches that the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (See pages 293-295). While some publications acknowledge that CDR3 is important for antigen binding, the conformations of other CDRs as well as the framework are equally important in antigen binding. For example, MacCallum et al. (Journal of Molecular Biology, 262:732-745, 1996) analyzed antigen-contacting residues and combining site shape of various antibodies and state that although CDR3 of the heavy chain and light chain dominate, a number of residues outside of the standard CDR definitions make antigen contacts (See page 733) . MacCallum et al. teach that antigens tend to bind to the antibody residues located at the center of the combining site where the six CDRs meet (See abstract and page 742) and less central CDR residues are only contacted by large antigens (See page 733 and 735). MacCallum et al. further teach that non-contacting residues are important in defining "canonical" backbone conformations.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is further underscored by Casset et al. (Biochemical and Biophysical Research Communications, 307:198-205, 2003), which discuss the importance of multiple CDRs in antigen contact. Casset et al. teach that all antibodies have six CDR residues, all of which are more or less involved in antigen recognition (See page 199). Casset et al. teach that peptide mimetics of antibody combining sites have previously only targeted CDR H3, since this CDR is typically at the center of most, if not all, antigen interactions; however this strategy is flawed since other CDRs play an important role in the recognition of antigen (See page 199). Casset et al. construct a peptide mimetic of an anti-CD4 monoclonal antibody, containing antigen contact residues from five CDR regions, except L2 and additionally using a framework residue located just before the H3 and show that the peptide has high binding to CD4, thus signifying the contribution of multiple CDRs, and not a single CDR, in antigen recognition (See page 202 and Figure 4). Vajdos et al. (Journal of Molecular Biology, 2002 Jul 5;320(2):415-28) additionally states that, “ ... Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.
Further, Sela-Culang et al. 2013 (The structural basis of antibody-antigen recognition; Frontiers in Immunology 4(302):1-13) teach the hypervariable loops within the variable domains of antibody polypeptides are widely assumed to be responsible for antigen recognition while the constant domains are believed to mediate effector activation, but that recent analysis indicates that their clear functional separation between the two regions is an over-simplification (see abstract). Sela-Culang et al. teach some residues within the CDRs may not participate in antigen binding and some residues outside the CDRs (e.g. in framework regions and in the constant domains) often contribute critically to the integration with the antigen (see abstract). Sela-Culang et al. teach understanding the role of each structural element is essential for successful engineering of binding polypeptides (e.g. page 2, left column). Sela-Culang et al. teach almost all of the residues predicted to be part of an epitope may be considered as correct predictors as they will bind to some antibodies but also are false predictors as they don’t bind to the others and accordingly that predicting that a residue is not in an epitope may be either a true negative or a false negative depending on the anybody considered (page 2, right column). Sela-Culang et al. teach each CDR has its own unique amino-acid composition different from the composition of the other CDRs and that each CDR has a unique set of contact preferences favoring certain amino acids over others (page 5-6, bridging). Sela-Culang et al. teach the combined action of all six CDRs is the evolutionary response of the immune system that enables the antibody polypeptide to recognize virtually any surface patch on the antigen (page 6). Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the antibody per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Accordingly, one of skill in the art would conclude that the claimed invention encompasses a plurality of antibodies comprising fewer than six CDRs that may not have the biological functions recited in the claims. It should be noted that the claimed invention encompasses the anti-interleukin 11 (IL-11) antibody, or an antigen-binding fragment thereof that inhibits IL-11-mediated signaling. Based on the teachings of the instant specification and the prior art, one of skill in the art would not conclude that Applicant was in possession of the claimed genus of antibodies.
Therefore, the species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115).
The arguments and examiner’s response address the CDR portion of the written description rejection.
Applicant’s Arguments
Applicant’s arguments (pp. 8-20, remarks received 18 February 2026) have been fully considered but are not found to be persuasive for the following reasons.
Applicant argues that the claims only allow for a single amino acid substitution in two of the recited CDR sequences, and that a skilled artisan would have recognized that Applicant was in possession of this narrow genus.
Response to Arguments
This has been fully considered but is not found to be persuasive for the following reasons. HD-CDR2 and LC-CDR2 are redacted from claims 31 and 34. The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is further underscored by Casset et al. (Biochemical and Biophysical Research Communications, 307:198-205, 2003), which discuss the importance of multiple CDRs in antigen contact. Casset et al. teach that all antibodies have six CDR residues, all of which are more or less involved in antigen recognition (See page 199). Casset et al. teach that peptide mimetics of antibody combining sites have previously only targeted CDR H3, since this CDR is typically at the center of most, if not all, antigen interactions; however this strategy is flawed since other CDRs play an important role in the recognition of antigen (See page 199). Casset et al. construct a peptide mimetic of an anti-CD4 monoclonal antibody, containing antigen contact residues from five CDR regions, except L2 and additionally using a framework residue located just before the H3 and show that the peptide has high binding to CD4, thus signifying the contribution of multiple CDRs, and not a single CDR, in antigen recognition (See page 202 and Figure 4).
Additionally, Applicant claims a single amino acid substitutions in SEQ ID NO: 30 and 31. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of a single amino acid substitution for example, in the polypeptide set forth in SEQ ID NO: 30 that is 119 amino acids in length translates into almost 1% variance that may be substituted anywhere throughout the entire length of the 119 residue amino acid polypeptide. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. Applicant have not described which domain or portions of SEQ ID NO: 30 and 31 are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of polypeptides, while maintaining any given function. Therefore, these structures (i.e., sequence variants and fragments) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences). Thus, in accordance with the cited case law, the rejection is maintained.
Conclusion
13. No claims are allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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