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 .
DETAILED ACTION
Formal Matters
Applicant’s amended specification and Sequence Listing in ST.25 format filed January 23, 2026 has been received and entered. Accordingly, the objection to the Sequence Listing filed December 16, 2025 for being in ST.26 format has been withdrawn.
Claim Status
Applicant’s amendment filed December 16, 2025 was received and entered.
Claims 1-22 are pending and under consideration.
Election/Restrictions
Applicant’s election without traverse of a single species of anti-IL-4Ra antibody in the reply filed on December 16, 2025 is acknowledged.
Applicant has elected without traverse:
The antibody of claim 5 part (7), comprising heavy chain CDRs: HCDR1-SEQ ID NO: 52, HCDR2-SEQ ID NO: 36, and HCDR3-SEQ ID NO: 37; light chain CDRs: LCDR1-SEQ ID NO: 53, LCDR2-SEQ ID NO: 54, and LCDR3- SEQ ID NO: 55, with VH/VL sequences of SEQ ID NOs: 19 and 20, respectively.
However, after further consideration all species were examined.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/CN2021/088139 filed April 19, 2021 which claims the benefit of foreign application China 202010331685.3 filed on April 24, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
However, support for the claimed invention cannot be determined because the foreign priority documents provided for Application No. CN202010331685.3 are not in English. Applicant cannot rely upon the certified copy of the foreign priority application to overcome any prior art rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216. Failure to provide a certified translation may result in no benefit being accorded for the non-English application. Accordingly, the PCT/CN2021/088139 filing date of April 19, 2021 will be used for the purpose of applying prior art.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 10, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1-6, 11, 14-16, and 20 are objected to for the following informalities:
Claims 1-6 recite SEQ ID NOs, which should be annotated with a colon, for example, SEQ ID NO: 1.
Claims 2-4 list the amino acid residues epitope binding of the claimed anti-IL-4Ra antibody using different formats. Claim 2 uses numbered parenthesis (1)-(6), claim 3 uses a combination of numbered circles ①-③and letters in parenthesis (A)-(E), while claim 4 uses the letter “P” and numbers (P-1)-(P-6). Applicant is advised to annotate the epitope residues as either numbers in parenthesis, or letters in parentheses as recited in claim 2 and 3, respectively.
Claim 3 - should read “has no cross-species binding activity”.
Claim 5 (lines 6, 8, 10, 14, 16, and 18) - recite “and, LCDR1”, however, should read “and LCDR1”.
Claim 11 (line 2) - should read “or a host cell transformed or transfected with the…”.
Claim 14 (lines 1-3) - should read, “Use of the antibody or antigen-binding fragment thereof, the nucleic acid molecule, the vector , the host cell , or the composition according to claim 12…”.
Claim 15 (line 6) - should read, “or is associated”.
Claim 16 - Crohn’s disease, Kaposi’s sarcoma, Hodgkin’s and non-Hodgkin’s lymphoma should be capitalized.
Claim 20 (lines 8-10) - should read “comparing the binding activity or affinity of the agent to the human IL-4R or part thereof after the mutation with the binding activity or affinity of the agent before the mutation”.
Claim 21 (parts 2 and 3) - should read “contacting an agent to be screened or an agent to be evaluated with the human IL-4R or part thereof and the mutant of the human IL-4R or part thereof, respectively, and detecting the binding activity or affinity thereto, respectively;
3) identifying agent capable of binding to the epitope, if the binding activity or affinity of the agent to the mutated human IL-4R or part thereof, respectively, is significantly lower or even lost compared with the binding activity or affinity of the agent to the human IL-4R or part thereof, respectively.
Claim 22 (line 4) - alanine should not be capitalized.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-3 and 5-22 are rejected under 35 U.S.C. 112(b) as 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.
Claims 1-3 are directed to an antibody binding to an epitope which comprises certain amino acids as recited in the claims. However, it is unclear whether the claims are referring to an epitope containing one or more of the recited residues such as D92, or an epitope containing all of the recited residues. For the sake of compact prosecution, the examiner will construe that the antibody binds, for example, epitope D92 or D92 and V94.
Claims 5-22 are included in the rejection because they depend from or otherwise require all the limitations of a rejected claim and fail to clarify the issue.
Claims 2-3, 5, 7-8, 13, 16-17, 20, and 22 are rejected under 35 U.S.C. 112(b) as 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.
Claims 2-3, 5, 7-8, 13, 16-17, 20, and 22 recite the limitations “preferably”, “more preferably”, and “further preferably”. The use of the phrase “preferably” in claims 2-3, 5, 7-8, 13, 16-17, 20, and 22 render the claims indefinite because one cannot ascertain the metes and bounds of what is and what is not allowed. The examiner contends that the use of such preferences may lead to confusion over the intended scope of the claim. See MPEP § 2173.05(d).
Claim 5 is rejected under 35 U.S.C. 112(b) as 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.
Claim 5 (lines 20-28) recites amino acid sequences and corresponding SEQ ID NOs for the heavy chain and light chain variable regions, “or an amino acid sequence having at least 75% identity to the amino acid sequence”. It is unclear which amino sequence is “the amino acid sequence” which the VH and VL can have 75% identity to.
Claims 8 and 15-17 are rejected under 35 U.S.C. 112(b) as 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.
Claims 8 and 15-16 recite the phrases “for example” and/or "e.g.", which render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 17 is included in the rejection because it depends from or otherwise requires all the limitations of a rejected claim and fails to clarify the ambiguity.
Claim 14 is rejected under 35 U.S.C. 112(b) as 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.
The claim as written can be interpreted as both a product and a method of using the product.
The claim recites “use of the antibody or antigen-binding fragment thereof,…or composition comprising said antigen-binding fragment”, which suggests a product composition comprising an anti-IL4Ra antibody and administering the antibody in separate steps. Thus, it is unclear if the claims are intended to encompass a composition comprising an anti-IL4Ra antibody which has an intended use in the steps of a process of preventing, treating, or ameliorating a disease or disorder associated with IL-4R or IL-4 and IL-13 signaling, or if the claims are intended to encompass a method of preventing, treating, or ameliorating a disease or disorder associated with IL-4R or IL-4 and IL-13 signaling comprising administering said anti-IL4Ra antibody. In the interest of compact prosecution, for the purposes of applying art, claim 14 has been construed as a method of treating/ameliorating a disease by administering an anti-IL-4Ra antibody.
Claims 16-17 and 20 are rejected under 35 U.S.C. 112(b) as 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.
Claims 16 and 20 recite the phrase "such as", which render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 17 is included in the rejection because it depends from or otherwise requires all the limitations of a rejected claim and fails to clarify the ambiguity.
Claim 17 is rejected under 35 U.S.C. 112(b) as 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.
Claim 17 recites the limitation “the medicament”. There is insufficient antecedent basis for this limitation in the claim.
Claims 20-21 are rejected under 35 U.S.C. 112(b) as 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.
The term “significantly lower” in claims 20-21 is a relative term which renders the claims indefinite. The term “significantly lower” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 22 is rejected under 35 U.S.C. 112(b) as 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.
Claim 22 recites the limitation “step 1)” in lines 3 and 10. There is insufficient antecedent basis for this limitation in the claim.
Claim 22 is rejected under 35 U.S.C. 112(b) as 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.
Claim 22 recites one or more amino acid residues comprised by the epitope are mutated to alanine or to an amino acid residue of the cynomolgus interleukin 4 receptor at the corresponding position”. However, no amino acid sequence is provided for the cynomolgus interleukin 4 receptor. Therefore, one cannot ascertain which corresponding amino acids of the cynomolgus interleukin 4 receptor protein can be substituted if the cynomolgus interleukin 4 receptor amino acid sequence is not provided.
Claim 22 is rejected under 35 U.S.C. 112(b) as 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.
Claim 22 (lines 6-7) recites “preferably, the part of human IL-4R is the alpha chain of human IL-4R, further human sIL-4Ra”. It is unclear if “further human sIL-4Ra” limits the claim to only soluble human IL-4Ra or if other forms of human IL-4Ra can also be used. The examiner contends that the use of such preferences may lead to confusion over the intended scope of the claim. See MPEP § 2173.05(d).
Claim 22 is rejected under 35 U.S.C. 112(b) as 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.
Claim 22 -- “Table 3” is recited within the claims. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. See MPEP § 2173.05(s).
Claim Rejections - 35 USC § 112(a) - Written Description
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.
Claims 1-4 and 6-22 are rejected under 35 U.S.C. 112(a), 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, at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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, sufficient to show the applicant was in possession of the claimed genus. See MPEP § 2163.
Claim 1 is drawn to an antibody or antigen binding fragment thereof, that binds to an epitope located on the alpha chain of human IL-4R (IL-4Ra) and comprises one or more of amino acid residues D92, V94, D97, L67, L68, A96, H156, C207, Q63, and L64 in the amino acid sequence set forth in SEQ ID NO: 1.
Claim 6 further defines the amino acid SEQ ID NOs for the heavy and light chain variable regions. However, does not define the 6 CDR regions.
The claims encompass a large genus of antibodies that bind to IL-4Ra, comprised of different combinations of heavy and light chain amino acid sequences, respectively, which represent structurally distinct polypeptides. As currently written, the structure of the claimed antibodies cannot be determined without defining the 6 CDR regions.
The state of the art is such that antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. As taught by Janeway et al. (2001), the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. See also Rabia et al. (2018; pg. 4), which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity. Additionally, the claims encompass a broad genus of structurally different antibodies derived from both human and nonhuman species, that would have different VH and VL sequences with different affinities or pharmacokinetic properties.
The state of the art is such that antibody production is extremely complex and requires a deep understanding of protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system. The development of candidate antibodies involves a complex process of clinical and preclinical evaluation that include identification of the physical and chemical properties of the antibody (Scott et al., 2012; pg. 278-279). Antibodies have a wide range of pharmacokinetics, effector functions, size and immunogenicity, affinities and avidities, all of which effect the function of each antibody in vivo (Scott, pg. 278). Furthermore, antibodies can have various effector functions including receptor blockage, reducing signaling, or in vivo cell depletion, and that antibody isotype alone is not predictive of in vivo function (Chan et al., 2010, pg. 307).
The art recognizes that the function of binding antibodies is extremely complex and unpredictable. The in vivo impact of a therapeutic monoclonal antibody is determined by both its epitope specificity (e.g., blocking or non‐blocking of ligand interactions) and heavy‐chain constant region (Fc) effector function (e.g., depleting or non‐depleting). Varying the Fc properties of an antibody can significantly affect the biological impact in vivo, and mutations in the heavy chain constant region have been shown to have highly divergent Fc effector function, without changing antibody specificity (Huss et al., 2016, p. 276).
The specification discloses the structure (i.e., amino acid sequence) of 7 humanized antibodies [pg. 27-29]. However, only some of the IL-4Ra antibodies that were generated bind to the epitopes recited in the instant claims. In fact, the instant specification discloses that with respect to positions L67 and L68 of the amino acid sequence of human IL-4Ra, when either L67 or L68 were mutated individually, the humanized antibodies maintained their original binding activity [pg. 38]. Therefore, the instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of antibodies encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002). In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir. 1997)).
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 Vas-Cath, p. 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, p. 1116).
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broad class of antibodies that bind the recited epitopes of the alpha chain of human IL-4R (IL-4Ra), in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claims 2-4 and 7-22 are included in the rejection because they depend from or otherwise require all the limitations of a rejected independent claim.
Claims 5-6 are rejected under 35 U.S.C. 112(a), 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, at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or 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, sufficient to show the applicant was in possession of the claimed genus. See MPEP § 2163.
Claims 5 and 6 recite the amino acid sequences of the anti-IL-4Ra antibody CDR regions and heavy and light chain variable regions, respectively. However, the claims also allow for an amino acid sequence having at least 75% identity to the amino acid sequence recited in claims 5 and 6. As such, one of ordinary skill in the art cannot ascertain the structure or binding affinity of an antibody having 75% identity to the sequences recited in claims 5 and 6. Therefore, the claims encompasses a large genus of structurally distinct polypeptides.
The art recognizes that the IL-4/IL-13 signaling pathway plays a central role in Th2-driven immune responses and is primarily associated with allergic and inflammatory diseases, including allergic asthma. However, as taught by Wills-Karp (2015), the exact signaling events mediating the distinct functions of IL-4R and IL-13 is complex and the exact mechanisms involved remain obscure [see Abstract and pg. 2, par. 1]. Kim et al. (2019) teaches that although antibodies targeting IL-4 or IL-13 have been developed, these Abs have not shown any favorable therapeutic benefits in clinical trials for asthma, suggesting that blocking IL-4 or IL-13 alone might be insufficient because of the redundancy in their signaling pathways. More recently focus has centered on blocking activation of IL-4Rα which is utilized by both IL-4 and IL-13, such as the commercially available anti-human IL-4Rα antibody, dupilumab, for the treatment for atopic dermatitis and asthma. However, other human IL-4Rα antibodies such as AMG 317, a human IgG2 Ab against IL-4Rα, did not demonstrate favorable clinical efficacy across patients with moderate to severe atopic asthma in phase II clinical trials [pg. 1-2], illustrating that anti-IL-4Rα antibody variants possess drastically different and unpredictable biological activity, despite having high affinity to IL4-Ra.
The instant disclosure does not disclose any means (i.e., substitution, deletion) in which the variable heavy chain or variable light chain amino acid sequences can be mutated resulting in a polypeptide 75% identical to the original sequence. When considering only amino acid substitutions in the VH and VL amino acid sequences comprising of 107 AA or 118 AA, each sequence can have up to 27 and 30 substitutions, respectively, to result in a VH or VL variable domain having 75% identity to the original sequence. Therefore, it can be considered that the inventions defined by claims 5 and 6 encompass a multitude of possible substitutions.
It is well understood in the art that protein folding and formulation are complex and fairly unpredictable processes, in such that substituting even one amino acid within the sequence can change the structure and function of said protein. Thus, one cannot readily extrapolate the properties of the polypeptide represented by the SEQ ID NOs recited in claims 5 and 6 to other possible sets of mutations, as the properties of the protein having an amino acid sequence of any VH or VL domain recited in claims 5-6, are not predictive of the full genus of proteins that can be generated.
The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of polypeptides encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002). In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir. 1997)).
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 Vas-Cath, p. 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, p. 1116). Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in
“possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support
need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein
v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —
i.e., what the written description and knowledge in the art would lead one to speculate as to
modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also
ensures that when a patent claims a genus by function, the specification recites sufficient materials to
accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3.
Given the broadly claimed class of polypeptides, in the absence of sufficient disclosure of relevant
identifying characteristics, the patentee must establish “a reasonable structure-function correlation”
either within the specification or by reference to the knowledge of one skilled in the art with functional
claims. There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed polypeptides to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claim Rejections - 35 USC § 112(a) - Enablement
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.
Claims 14-17 are rejected under 35 U.S.C. 112(a), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 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, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Claims 14-15 and 17 are drawn to preventing, treating, or ameliorating a disease or disorder associated with IL-4R or IL-4 and IL-13 signaling by administering an anti-IL4Ra antibody. Claim 16 further recites that the disease or disorder includes an autoimmune disease, an allergic disease, a tumor, or a cancer.
The specification does not provide any definition for “prevention”. Therefore, the plain meaning of the term preventing and prevention as recited in claims 14-15 and 17 will be interpreted as including up to 100% prevention (see Merriam Webster definition: prevent. Accessed online 26 Jan 2026).
Regarding prevention, the current state of the art is that there is no way to prevent a person from developing an autoimmune disease, however, certain habits may reduce the risk or delay the onset. Current treatments focus on managing symptoms and preventing further damage (www.chilrenshospital.org). Similarly, the state of the art teaches that prevention of allergic disease has yet to be achieved. Kun et al. (2016), teaches allergic diseases comprise food and drug allergies, allergic rhinitis, asthma, urticaria and atopic dermatitis which affect 20-30% of the world population. However, because of the various underlying molecular mechanisms, there are no established methods to prevent them [Introduction]. Furthermore, Umar and Bode et al. (2009), teach cancer prevention is not about eliminating cancer altogether, but reducing risk factors and exposure with the goal of inhibiting progression of cancer to more invasive stages [Umar; pg. 835, col. 2, par. 2; pg. 836, col. 1, par. 2; pg. 839, col. 2, par. 2-3] [Bode; pg. 511, col. 3, par. 2]. Moreover, Sarfati et al. (2022) teaches that primary prevention of cancer through eradication or mitigation of modifiable risk factors is the best hope of reducing the future cancer burden [pg. 541, col. 1]. Even vaccination has yet to achieve 100% prevention of cancer, as seen with the hepatitis B virus (HBV) vaccine, which has an estimated 69% reduction rate in prevention of hepatocellular cancer (HCC), however cannot 100% prevent it [Umar; pg. 842, col. 1, par. 3]. Although cancer vaccines can serve as preventive measures in high-risk populations and provide treatment options for individuals already diagnosed with cancer [Kaczmarek et al., 2023; pg. 2, par. 2], they also face a myriad of obstacles depending on the target, type of vaccine, delivery method, and type of cancer (Kaczmarek et al., pg. 21, section 7). Accordingly, the state of the current art is that cancer cannot be 100% prevented and there is a high degree of unpredictability in methods directed to prevention.
Applicant has not provided any examples of administering any of the claimed antibodies to achieve 100% prevention of a disease or disorder associated with IL-4R or IL-4 and IL-13 signaling or how to achieve 100% prevention.
Accordingly, in the absence of substantive direction or guidance in the instant specification, the entire scope of experimentation required to prevent a disease or disorder associated with human interleukin 4 receptor (IL- 4R) or a disease or disorder associated with human interleukin 4 (IL-4) or human interleukin 13 (IL-13) signaling pathway would be unnecessarily improper, extensive, and undue.
Claims 15-17 are rejected under 35 U.S.C. 112(a), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 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, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
Claim 15 is drawn to preventing, treating, or ameliorating a disease or disorder associated with IL-4R or IL-4 and IL-13 signaling by administering an anti-IL4Ra antibody. Claim 16 further recites that the disease or disorder includes an autoimmune disease, an allergic disease, a tumor, or a cancer.
Regarding treating or ameliorating a disease or disorder associated IL-4R or IL-4 and IL-13, it is known in the art that the association of IL-4R with disease is preliminary, and any link between human IL-4R or human IL-4/IL-13 signaling pathways is immature. The art recognizes that the IL-4/IL-13 signaling pathway plays a central role in Th2-driven immune responses and is primarily associated with allergic and inflammatory diseases, including allergic asthma. However, as taught by Wills-Karp (2015), the exact signaling events mediating the distinct functions of IL-4R and IL-13 is complex and the exact mechanisms involved remain obscure [see Abstract and pg. 2, par. 1]. Therefore, there is currently no clear range of diseases that correspond to these mechanisms.
Claim 16 recites specific autoimmune diseases, allergic diseases, tumors, or cancers that can be treated with the claimed antibody, which comprise a broad genus of indications. However, one skilled in the art cannot expect all autoimmune diseases, allergic diseases, tumors, or cancers to be associated with the human IL-4R or the IL-4 IL-13 pathway. Furthermore, Applicant has not provided any in vitro or in vivo examples demonstrating the claimed antibodies have any effect for the treatment or amelioration of any disease or disorder.
Accordingly, in the absence of substantive direction or guidance in the instant specification, the entire scope of experimentation required to treat or ameliorate a disease or disorder associated with human interleukin 4 receptor (IL- 4R) or a disease or disorder associated with human interleukin 4 (IL-4) or human interleukin 13 (IL-13) signaling pathway would be unnecessarily improper, extensive, and undue.
Claim 17 is included in the rejection because it depends from and requires all the limitations of a rejected independent claim.
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.
Claims 1-4, 7-12, and 14-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al. (Sci Rep, 2019; 23(9):7772) (“Kim”).
As set forth in the rejection above, instant claim 14 can be interpreted as both a product or a method. In the interest of compact prosecution, for the purposes of applying art, claim 14 has been construed as a method.
Kim discloses human anti-IL-4R antibodies (Abs) against interleukin-4 receptor alpha (IL-4Rα) subunit of IL-4/IL-13 receptors for blocking both IL-4- and IL-13-mediated type 2 inflammation [Discussion, pg. 7, par. 1] (instant claim 7). Kim performed antibody library screening and engineering to generate potent Abs against human IL-4Ra using yeast surface display technology. Ten Fabs with high affinity to IL-4Rα were isolated and converted into the conventional human IgG1 format [pg. 2, par. 3]. Specifically, the variable heavy and light regions (VH and VL) of isolated Fab clones were reformatted into the human IgG1 isotype through subcloning of respective VH and VL genes into a modified vector carrying the human IgG1 constant domain and a vector carrying the human kappa constant domain, respectively [Methods, pg. 8] (instant claims 8-10). Additionally, the clinically approved anti-IL4-Ra antibody dupilumab was modified to have the constant region of human IgG1 isotype rather than the IgG4 isotype of dupilumab. The plasmids encoding the Abs were transiently transfected into HEK293F cell cultures (instant claim 11). The isolated Abs showed concentration-dependent binding to IL-4Ra at varying levels [pg. 2, par. 3]. The antibody with the greatest IL-4 blocking activity was selected for affinity maturation by CDR mutations. Again, the isolated Fab clones were reformatted as human IgG1 [pg. 3, par, 2]. Kim discloses the engineered human IgG1 Ab 4R34.1.19 specifically binds to IL-4Ra with high affinity to competitively block the ligand binding to IL-4Ra, thereby suppressing both IL-4- and IL-13-dependent signaling in ex vivo assays with human immune cells at comparable levels of the dupilumab analogue. Kim found that 4R34.1.19 differed from the dupilumab analogue particularly in the binding epitopes and kinetics [pg. 2, par. 2].
Subsequently, Kim carried out epitope mapping on Abs 4 R34.1 and 4 R34.1.19 to identify the binding epitopes of the Abs by alanine scanning mutagenesis focusing on 8 residues of IL-4Rα, located in the interface with the ligands of IL-4/IL-13 (instant claim 22). Eight alanine mutants of IL-4Rα were screened for Ab binding via ELISA (instant claim 18). The isolated anti-IL-4Ra Abs lost binding activity at varying degrees for the alanine mutants at residues L67, L68, D92, V93, and D97 (Fig. 4c, Supplementary Fig. 4c), indicating that they mainly recognize the ligand binding regions on IL-4Ra, but their epitopes are slightly different to each other (instant claims 1-2). Furthermore, the binding profile of 4 R34.1.19 for the alanine mutants were much different from that of the dupilumab analogue, indicative of their different epitopes on IL-4Ra. Candidate antibody 4 R34.1.19 had a significant loss in binding to IL-4Ra mutants carrying an alanine substitution at IL-4 binding sites L68, V93 and D97, whereas the dupilumab analogue demonstrated a slight reduction in binding to V93A and D97A mutants [pg. 6, par. 1] (instant claims 4, 19-21).
Kim further assessed the ability of 4 R34.1.19 to inhibit IL-4-induced differentiation of naïve CD4+ T cells into TH2 cells, given the role of IL-4in in promoting TH2 responses, finding the potency of 4 R34.1.19 comparable to the dupilumab analogue (instant claim 12). IL-4-mediated CD4+ T cell proliferation and differentiation into TH2 are the upstream events triggering the inflammatory cascade in allergic diseases [pg. 8, par. 1]. In addition, naïve CD4+CD45RO− T cells purified from PBMCs of asthmatic patients treated with 4 R34.1.19 substantially inhibited IL-4-mediated differentiation of patient-derived naïve CD4+ T cells into TH2 cells at comparable levels to dupilumab analogue, indicating the potential of 4R34.19 as a therapeutic antibody for the treatment of allergic diseases (instant claims 14-17) [pg. 7, par. 1; pg. 8, par. 2].
Kim explains that 4R34.1.19 does not cross-react with mouse IL-4Rα because of the low sequence identity (~50%) in the ectodomain of IL-4Rα between human and mouse, thus, in vivo efficacy could not be evaluated. Although 4 R34.1.19 has lower affinity with IL-4Rα than the dupilumab analogue, it was distinguished from the dupilumab analogue in the binding epitopes, indicating that both affinity and epitope are the critical factors to determine the biological activity of anti-IL-4Rα Abs. These different properties of 4R34.1.19 may lead to differential therapeutic applications than dupilumab [Discussion, pg. 8].
As can be derived from the sequences of the heavy and light chain variable domains of the 4R34 antibodies in Supplementary Figure 2, the CDRs are very similar to the CDRs of the claimed antibodies, while there are some differences in the framework regions (instant claim 3).
The instant specification discloses SEQ ID NO: 1 is the amino acid sequence of human sIL-4Ra [pg. 17, lines 16-17].
In view of the fact that the anti-human IL-4Ra antibodies disclosed by Kim share an overlapping epitope with antibodies of the instant invention, and taking into account the high degree of identity in their CDR amino acid sequences, in the absence of evidence to the contrary, it is considered that the antibodies disclosed by Kim would not cross-react with cynomolgus IL-4R as recited in claim 3.
Therefore, absent a showing of any difference, the anti-human IL-4Ra antibodies disclosed by the prior art are deemed to anticipate the anti-human IL-4Ra antibodies recited in the instant claims.
Claim Rejections - 35 USC § 103
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.
Claims 1 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al. (Sci Rep, 2019; 23(9):7772) (“Kim”) as applied to claims 1-4, 7-12, and 14-22 above, and in further view of Zheng et al. (US 2019/0177408) (“Zheng’).
The instant claims are drawn to an antibody or antigen-binding fragment thereof that binds to human interleukin-4 receptor (IL-4R), the antibody or antigen-binding fragment thereof binding to an epitope which is located on the alpha chain of human IL-4R (IL-4Ra) and comprises one or more of amino acid residues D92, V94, D97, L67, L68, A96, H156, C207, Q63, and L64 in the amino acid sequence set forth in SEQ ID NO. 1. Also claimed is a nucleic acid molecule comprising a nucleotide sequence encoding the antibody, a vector comprising the nucleic acid molecule, a host cell comprising the nucleic acid molecule or vector, a composition comprising the antibody, vector comprising the nucleic acid molecule, or a host cell comprising the nucleic acid molecule or vector, wherein the composition is a pharmaceutical composition.
The teachings of Kim are set forth above.
Kim does not explicitly teach a pharmaceutical composition comprising the IL-4Ra antibody or antigen- binding fragment, the nucleic acid molecule, the vector, or the host cell comprising said antibody.
Zheng teaches an antibody capable of binding to the interleukin 4 (IL-4) receptor (IL-4 ), a nucleic acid sequence encoding the antibody, a vector including the nucleic acid sequence, and a host cell transformed or transfected with the vector. Zheng further teaches a method for producing the antibody and a medical use of the antibody [Abstract]. The antibody, nucleic acid sequence, vector or host cell may be contained in a pharmaceutical composition, and may further comprise a pharmaceutically acceptable carrier or excipient [0210, 0212]. Zheng further teaches the antibody can be used for preventing, treating or ameliorating inflammation or allergic disease by administering to a subject (preferably a human) the antibody, nucleic acid sequence, vector, or host cell; wherein the inflammation or allergic disease includes autoimmune disease, such as allergic dermatitis, asthma, eosinophilic esophagitis, eczema, allergic rhinitis, nasal polyps, and rheumatoid arthritis [0216, 218].
The teachings of Kim differ from the instant invention in that even though anti-human IL-4Ra antibodies that bind to the specific epitopes of human IL-4Ra recited in the instant claims for the treatment of allergic diseases is disclosed, the antibodies are not explicitly taught as being formulated in a pharmaceutical composition. However, Kim discloses the candidate antibody has therapeutic potential as a treatment for allergic diseases [pg. 8, par 2]. Therefore, it would have been obvious to one of ordinary skill in the art that the antibodies disclosed by Kim have an intended use in a pharmaceutical composition for the treatment of human subjects with allergic diseases such as allergic asthma. One would have more than a reasonable expectation of success in formulating the antibodies of the instant invention in a pharmaceutical composition, as pharmaceutical compositions comprising human IL-4Ra antibodies have demonstrated therapeutic potential against a variety of allergic diseases as evidenced by Zheng. Accordingly, the combination of prior art references provided a prima facie case of obviousness for the instantly claimed invention.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642