DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed on 12/11/2023, is acknowledged.
Claim 10 is cancelled.
Claims 1-9 and 11-21 are currently pending.
Claims 1, 3, and 9 are independent claims.
Election/Restrictions
Applicants’ election with traverse of Group I, claims 1-9, 11, 12, and 16-18, directed to an isolated anti-IL-36R antibody and the Species of the 72C1 antibody clone structure, filed on 6/17/2026, is acknowledged. The traversal is on the grounds that: 1) there is not a complete search for prior art; and 2) the generic claims do not place an undue burden on the Office for search. This is not found persuasive because 1) the Groups of Invention were found to lack unity of invention over the prior art, as discussed in the Restriction Requirement mailed on 5/15/2026, and 2) the Species are deemed to lack unity of invention as discussed in the Restriction Requirement mailed on 5/15/2026.
The requirement is still deemed proper and is therefore made FINAL.
Claims 13-15 and 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Claims 1-12 and 16-18 are under examination as reading on an isolated IL-36R antibody comprising the CDRs and VH/VL of the 72C1 antibody clone.
The elected species of antibody recited in instant claim 3 is free of the prior art. The search and examination has been extended to other species in the claim.
Priority
Applicant’s claim for the benefit of a prior-filed Chinese Patent Application No. 202110675925.6 filed on June 18, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 4/19/2024, 7/22/2025, and 5/22/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, browser-executable code is disclosed in the specification on pg. 37, line 16 (“www.fortebio.com”). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms:
TWEEN® (pg. 37, line 24);
GraphPad Prism® (pg. 38, line 2; pg. 39, line 17; pg. 40, line 3);
Lipofectamine™ (pg. 38, lines 10 and 15);
MabSelect SuRe™ (pg. 44, line 5);
Nanodrop™ (pg. 44, line 7); and
Superdex™ (pg. 44, line 7);
which are trade names or marks 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.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 9 is 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 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claim 9 requires anti-IL-36R binding antibodies with no recited structure and the function of “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1”. While the amino acid sequences of the anti-IL-36R antibodies recited in claim 1 are disclosed in the specification, immunizing an animal with IL-36R will generate antibodies directed to a number of different epitopes within IL-36R and not necessarily to the same epitope which is bound by the claimed antibodies in instant claim 1. The knowledge of the amino acid sequence of IL-36R, by itself, did not put Applicants in possession of antibodies that compete for binding with claimed anti-IL-36R antibodies.
In determining that the specification did not support the claimed anti-IL-36R antibodies, the disclosure is considered. The specification fails to disclose a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. Two of these factors described in the specification were a function recitation of competition for binding (pg. 27) and the structure of the IL-36R epitope (Example 1). Thus, the skilled artisan could not envision the detailed chemical structure of the encompassed genus of antibodies until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Absent a recitation of distinguishing identifying characteristics, the disclosure does not provide adequate written description support of the claimed genus.
The Federal Circuit has recognized that "the written description requirement can in some cases be satisfied by functional description," it has made clear that "such functional description can be sufficient only if there is also a structure-function relationship known to those of ordinary skill in the art." In re Wallach, 378 F.3d 1330, 1335 (Fed. Cir. 2004); see also, Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 964 (Fed. Cir. 2002) (holding that the written description requirement would be satisfied "if the functional characteristic of preferential binding ... were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed"); Amgen Inc. v. Sanofi, 782 F.3d 1367, 1378 (Fed. Cir. 2017) (holding that an "adequate written description must contain enough information about the actual makeup of the claimed products"). Here, the specification provides a functional description of the claimed antibody- i.e., that it competes for binding to anti-IL-36R antibodies recited in instant claim 1, but the specification does not identify any disclosure of a correlation between the claimed function and the structure of the antibodies that perform that function.
Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed encoded anti-IL-36R antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
For instance, citing to Centocor, the Court analogized an antigen and antibody to a lock and a key. For an antigen where there is only a finite number of binding antibodies, discovering those antibodies may be routine and conventional, and description of the antigen alone may be sufficient. By contrast, for antigens with millions of keys, or millions of potentially binding antibodies, description of the antigen and even a couple of examples may be far from sufficient.
This case is thus similar to Centocor Ortho Biotech, Inc. v. Abbott Laboratories, 636 F.3d 1341 (Fed. Cir. 2011). In Centocor, patentee claimed an antibody or antibody fragment that competitively inhibits binding of A2 (a mouse antibody) and that binds an epitope of TNF-α with a specified affinity. 636 F.3d at 1346. Both TNF-α protein and antibodies to that protein were known in the literature. Id. at 1352. Patentee argued that the patent at issue satisfied the written description for the claimed antibodies because it "not only describes the antibodies by their binding affinity for TNF-α, but further describes the antibodies by specifying that they competitively inhibit binding of the A2 mouse antibody to TNF-α." Id. At 1349. The Federal Circuit rejected this argument, finding that "[a]t bottom, the asserted claims constitute a wish list of properties that a fully-human, therapeutic TNF-α antibody should have: high affinity, neutralizing activity, and the ability to bind in the same place as the mouse A2 antibody." Id. At 1351. The court explained that "[t]he specification at best describes a plan for making fully-human antibodies and then identifying those that satisfy the claim limitations."
In finding that the specification at issue did not provide written description support for the claimed antibodies, the Centocor court recognized that the written description does not require examples or an actual reduction to practice, but clarified that "it does demand ... that one of skill in the art can 'visualize or recognize' the claimed antibodies based on the specification's disclosure." Id. at 1353. "In other words, the specification must demonstrate constructive possession." Id; see also, AbbVie Deutschland GmbH & Co., KG., v. Janssen Biotech, Inc., 759 F.3d 1285, 1301 (Fed. Cir. 2014) (reiterating requirement for structure-function correlation in functionally defined claims and finding that the patents at issue do not meet the written description requirement because they "do not describe any common structural features of the claimed antibodies.").
Here, as in Centocor, Applicant seeks to ground written description support for a claimed antibody in its competitive inhibition of another antibody (here, the monoclonal antibodies recited in instant claim 1, in Centocor, mouse A2 antibody) and in the description of a known antigen (here IL-36R, in Centocor, TNF-α). While the state of the art has progressed since the Federal Circuit's decision in Centocor, the basic problem remains that the description at issue must allow one of skill in the art to "visualize or recognize" the claimed antibodies. Here, the evidence of record does not support that the skilled artisan would have visualized or recognized the claimed antibodies based on the description provided. As in Centocor, the Specification provides only a plan for identifying the claimed antibodies.
Possession is not to be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of anti-TIM-3 competing antibodies falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 1, 2, 4-9, 11, 12, and 16-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the structures of the antibody clones 72C1, hz72C1-1.1, hz72C1-1.2, hz72C1-1.3, hz72C1-2.1, hz72C1-2.2, hz72C1-2.3, 84C4, hz84C4-1.1, hz84C4-1.2, hz84C4-1.3, hz84C4-1.4, hz84C4-1.5, hz84C4-2.1, hz84C4-2.2, hz84C4-2.3, hz84C4-2.4, hz84C4-2.5, 74B4D6, 58A8D1, 6G10 with the function of “anti-IL-36R”, does not reasonably provide enablement for a broad genus of antibodies with a partial structure at best and the function of “anti-IL-36R”. 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.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Breadth of claims and nature of invention:
Claims 1, 2, 4-8, 11, 12, and 16-18 encompass a broad genus of antibodies with a partial structure at best and the function of “anti-IL-36R”, and claim 9 encompasses a broad genus of antibodies with no recited structure and the functions of “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1”.
For example, instant claim 1 encompasses a broadly claimed genus of antibody clones with the elected species of CDRs with up to 20% variation in each CDR region. The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula:
N
!
*
19
A
N
-
A
!
A
!
Where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. For the elected species of HCDR combination (SEQ ID NO: 1 + SEQ ID NO: 2 + SEQ ID NO: 3), which is 38 residues in length with 7 allowed substitutions (38x0.2), there would be
38
!
*
19
(
7
)
38
-
7
!
7
!
Which is approximately 4.2x1016 variants for this HCDR combination alone.
The specification discloses identification of antibody clones that specifically bind to IL-36R through immunization of mice followed by hybridoma formation and isolation (Example 2). 5 different clones were isolated from this screen, which are 72C1, 84C4, 74B4D6, 58A8D1, and 6G10 (Example 2). The 72C1 and 84C4 clones were then humanized to generate the humanized antibody clones hz72C1-1.1, hz72C1-1.2, hz72C1-1.3, hz72C1-2.1, hz72C1-2.2, hz72C1-2.3, hz84C4-1.1, hz84C4-1.2, hz84C4-1.3, hz84C4-1.4, hz84C4-1.5, hz84C4-2.1, hz84C4-2.2, hz84C4-2.3, hz84C4-2.4, hz84C4-2.5 (Example 9). All of these antibody clones are specific structures defined by their amino acid sequences, especially in the 6CDRs critical for antigen binding, with the function of “anti-IL-36R”, or “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1”.
Amount of direction and existence of working examples:
The instant specification discloses identification of the 72C1, 84C4, 74B4D6, 58A8D1, and 6G10, hz72C1-1.1, hz72C1-1.2, hz72C1-1.3, hz72C1-2.1, hz72C1-2.2, hz72C1-2.3, hz84C4-1.1, hz84C4-1.2, hz84C4-1.3, hz84C4-1.4, hz84C4-1.5, hz84C4-2.1, hz84C4-2.2, hz84C4-2.3, hz84C4-2.4, and hz84C4-2.5, all that were identified from hybridomas generated by immunization of mice with IL-36R (Example 2 and 9). The instant specification does not provide any guidance to determine how to identify different antibody structures with the function of “anti-IL-36R”, or “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1”.
Level of predictability, state of prior art, and quantity of experimentation needed:
The claims are directed to agents with little to no recited structure, all with the function of “anti-IL-36R” (claims 1, 2, 4-8, 11, 12, and 16-18) or “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1” (claim 9), which includes broad genera of millions to billions of different structures, including antibodies and other polypeptide structures, with the recited function.
However, the specification did not give the skilled in the art enough information to choose candidate antigen binding structures from the vast number of options of millions of candidates, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses a limited number of anti-IL-36R antibody examples with functions of “anti-IL-36R” (claims 1, 2, 4-8, 11, 12, and 16-18) or “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1” (claim 9).
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
In the instant case, the claims are directed to a broad class of antibodies or antigen binding fragments thereof with a partial structure at best and the functions of either “anti-IL-36R” (claims 1, 2, 4-8, 11, 12, and 16-18) or “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1” (claim 9), while the specification only discloses 21 different antibody examples with these functions.
The instant claims are directed to classes of antibodies or antigen binding fragments thereof that include “a ‘vast’ number” of additional structures (i.e., amino acid sequences of all of the CDR regions that are necessary for antigen binding) in which the instant specification fails to describe. It would be necessary to first generate and then screen each candidate agent to determine whether or not it met the function limitations of “anti-IL-36R” (claims 1, 2, 4-8, 11, 12, and 16-18) or “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1” (claim 9). The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant specification does not disclose any common structural feature delineating which other polypeptide structures would have the functions of “anti-IL-36R” (claims 1, 2, 4-8, 11, 12, and 16-18) or “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1” (claim 9). The only structure-function relationship guidance the specification provides is to disclose individual examples of anti-CD47 antibody structures and SIRPα-Fc fusion polypeptide structures with these functions.
Additionally, claims 1, 4, 6, 8, 11, 12, 16, and 17 encompass anti-IL-36R antibodies that include mixing and matching CDRs from different antibody clone structures. The specification discloses 21 anti-IL-36R antibodies, 72C1, 84C4, 74B4D6, 58A8D1, and 6G10, hz72C1-1.1, hz72C1-1.2, hz72C1-1.3, hz72C1-2.1, hz72C1-2.2, hz72C1-2.3, hz84C4-1.1, hz84C4-1.2, hz84C4-1.3, hz84C4-1.4, hz84C4-1.5, hz84C4-2.1, hz84C4-2.2, hz84C4-2.3, hz84C4-2.4, and hz84C4-2.5, which were not random combinations of VH and VL i.e., they had specific VH domains paired with specific VL domains. No other VH/VL domain was provided that mix, for example, the CDRH1-H3 of SEQ ID NO: 1, 2, and 3 with other CDRL1-3 domains other than SEQ ID NO: 4, 5, and 6, respectively (such as mixing the CDRH1-3 of the 72C1 clone with the CDRL1-3 of the 84C4 clone).
Neither the specification, nor the prior art provides any examples to support the premise of mixing and matching a HCDR or LCDR of the VH/VL of different antibodies would result in antigen binding. The prior art does not support a definition of an antibody structure by mixing and matching the HCDR1-3 sequence of a VH and/or LCDR of sequence of a VL and result in functional anti-TMPRSS6 antibodies. The specification fails to show that all HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3 of the 21 anti-IL-36R antibodies 72C1, 84C4, 74B4D6, 58A8D1, and 6G10, hz72C1-1.1, hz72C1-1.2, hz72C1-1.3, hz72C1-2.1, hz72C1-2.2, hz72C1-2.3, hz84C4-1.1, hz84C4-1.2, hz84C4-1.3, hz84C4-1.4, hz84C4-1.5, hz84C4-2.1, hz84C4-2.2, hz84C4-2.3, hz84C4-2.4, and hz84C4-2.5 are equivalent. The specification fails to establish that, for example, by replacing at least one different CDR of the 72C1 antibody with another CDRs from, for example, 84C4, 74V4D6, or 58A8D1, maintains specific IL-36R binding. Mixing and matching different CDRs from different anti-IL-36R antibodies has not been shown to lead to specific IL-36R binding. Such teachings were not made part of the specification at the time the invention was made.
It is unlikely that antibodies or fragments thereof as defined by the claims which may contain less than the full complement of CDRs from the heavy and light chain variable regions of the 72C1, 84C4, 74B4D6, 58A8D1, and 6G10, hz72C1-1.1, hz72C1-1.2, hz72C1-1.3, hz72C1-2.1, hz72C1-2.2, hz72C1-2.3, hz84C4-1.1, hz84C4-1.2, hz84C4-1.3, hz84C4-1.4, hz84C4-1.5, hz84C4-2.1, hz84C4-2.2, hz84C4-2.3, hz84C4-2.4, and hz84C4-2.5 antibodies fused to framework sequences, have the required binding function. The specification provides no direction or guidance regarding how to produce monoclonal antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone. Further, the specification does not teach that a functional antibody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 6 CDRs sequences of a donor antibody.
Additionally, claims 1, 2, 4-8, 11, 12, and 16-18 of the instant application encompass (but does not exemplify) fragments and CDR modifications up to 20% (deletion/addition/substitution) to the claimed HCDRs and LCDRs of SEQ ID NO: 1, 2, 3, 4, 5, and 6 (the elected invention). There is no teaching identifying what amino acids can be varied within the VH-CDRs or VL-CDRs antibody regions and still retain antibody or fragments capable of specifically binding to IL-36R. Brown et al. (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation 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. 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. The scope of the claims encompasses antibodies with VH or VL that encompass variation (additions, deletions, substitutions) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g., 6CDRs) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds IL-36R to satisfy the enablement requirement for the claims.
Regarding the amino acid substations in variable regions (claims 4, 5, 7), one skilled in the art would have recognized challenge and trade-offs once it is applied in antibody. Rabia et al. (Biochem Eng J. 2018 September 15; 137: 365-374) states that to optimize antibody properties (affinity, specificity, stability, solubility and effector functions) with amino acid substitutions is challenging and there is always trade-off. Rabia et al. further states that an outstanding challenge in the field is that optimizing properties such as antibody affinity can lead to defects in other properties such as antibody stability, specificity and solubility. The resulting trade-offs between improvements in some antibody properties and reductions in others highlight that they are often interdependent and cannot be easily separated (Introduction). Rabia et al. further state given that the maximal chemical diversity of antibody CDRs is unimaginably large (>1078 antibody variants based on 20 different amino acids at ~60 sites in the CDRs), it is extremely challenging to define the sequence determinants of antibody specificity (para 2).
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antibody structures they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
Applicant is relying upon certain biological activities such as inhibitory antibodies that bind to IL-36R and a limited number of species with defined structures (e.g. amino acid sequences) to support an entire genus of diverse and structurally unrelated inhibitory polypeptide structures. Yet the instant specification does not provide sufficient guidance and directions as to the structural features of the antibody structures and the correlation between the structure and the desired antigen binding and inhibitory function.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
Additionally, in its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be "materially indistinguishable from those in Amgen." Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers "millions of potential candidate antibodies" (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, "the '590 patent's roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose." (Id.) Missing from the specification, according to the Federal Circuit, was "'a quality common to every functional embodiment' ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions" (id.; quoting Amgen Inc. v. Sanofi., 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta's argument that its disclosed hybridoma-and screening process "predictably and reliably generates new claimed antibodies every time it is performed" (id.), because "it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions." (Id.).
The specification does not reasonably provide enablement to make and use the invention of instant claims 1, 2, 4-9, 11, 12, and 16-18. The specification does enable one with ordinary skill to make the antibody clone discussed supra.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
To overcome this rejection, it is recommended to amend the claims to recite the known and disclosed antibody structures, defined by their amino acid sequences in the 6CDR regions critical for binding, with the functions of “anti-IL-36R” (claims 1, 2, 4-8, 11, 12, and 16-18) or “binds to the same epitope as the antibody or antigen-binding fragment thereof according to claim 1, or competes with the antibody or the antigen-binding fragment thereof according to claim 1” (claim 9).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 9 is rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by Brown et al. (U.S. PGPub 20130236471).
Brown et al. teaches anti-IL-36R antibodies (Abstract). These antibodies bound IL-36-R and successfully interfered with IL36/IL36R signaling (Example 7; i.e., the limitations of instant claim 9).
Regarding the functional limitation “competes with the antibody or antigen-binding fragment thereof according to claim 1 for binding to IL-36R” recited in claim 9, the instant specification discloses that the antibodies of the instant application bind to IL-36R and interfere with IL36/IL-36R interactions (instant Specification “Brief Summary”): “…the antibody or the antigen-binding fragment thereof of the present disclosure is capable of binding to IL-36R (e.g., human and monkey IL-36R) with high affinity and blocking the IL-36/IL-36R interaction.” Thus, the antibodies of Brown et al., which also bind to IL-36R and interfere with IL36/IL36R interactions, would compete for binding with the antibodies of the instant application.
Brown et al. anticipates the limitations of instant claim 9.
Allowable Subject Matter
The anti-IL-36R antibody structures recited in claim 3 are free of the prior art.
Conclusion
Claim 3 is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Ganesan et al. (MAbs. 2017 Oct;9(7):1143-1154. doi: 10.1080/19420862.2017.1353853. Epub 2017 Jul 20) teaches anti-human and anti-mouse IL-36R antibodies (Abstract), such as the MAB04 clone (Fig. 5). However, Ganesan et al. does not teach the anti-IL-36R antibody structures recited in instant claim 3.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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