Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s amendments and remarks, filed 10/22/2025, are acknowledged.
Claims 1-22 are pending.
DETAILED ACTION
Election/Restrictions
Applicant’s group election without traverse of Group I, encompassing claims 1-13, 17, and 20-22, in the reply filed on 10/22/2025 is acknowledged.
Claims 14-16 and 18-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/22/2025.
Applicant's species election with traverse of the antibody as defined by item (14) of claim 10 in the reply filed on 10/22/2025 is acknowledged. The traversal is on the ground(s) that there is no serious burden on searching additional species, specifically, the antibody species as defined by items (8) to (13) in claim 10 are related with item (14). This is not found persuasive because the claims are not limited to items (8) to (13) of claim 10. The claims recite thousands of different species of anti-AREG antibodies each comprising different CDR sequences, including up to five modifications, and consequently different VH/VL sequences. As such, there is a serious search burden to search the large genus of anti-AREG antibodies claimed.
The requirement is still deemed proper and is therefore made FINAL.
As such, claims 1-13, 17, and 20-22 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/17/2023, 07/24/2023, 12/16/2024, 04/11/2025, 07/15/2025, and 08/26/2025 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because Figure 3 recites several protein sequences without providing the corresponding SEQ ID Nos (see Sequence Disclosures below).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See, e.g., paragraphs [0141], [0142], and [0160] of the specification filed 09/29/2022.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the drawings (i.e., Fig. 3) are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because of the following informalities:
Para. [013]: “an unique” should read “a unique”.
Para. [0158]: “ELSIA” should read “ELISA”.
Para. [0204]: “Cell Signaling technology” should read “Cell Signaling Technology”.
Appropriate correction is required.
The use of the term Dynabeads®, Life Technologies, Biacore, Sigma, Nunc, MaxiSorp™, GE Healthcare, Bio-Rad, Thermo Fisher Scientific, TRIzol, PrimeScript™, PeproTech, Thermo Fisher, Cell Signaling Technology, Sigma-Aldrich, and Charles River, which is 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.
Claim Objections
Claims 1-13, 17, and 20-22 are objected to because of the following informalities:
Claims 1-13, 17, and 20-22: “AREG” is an acronym and/or abbreviation which should be spelled out on first occurrence.
Claims 1 and 21: “IPF” is an acronym and/or abbreviation which should be spelled out on first occurrence.
Claim 5: “EGF” is an acronym and/or abbreviation which should be spelled out on first occurrence.
Claims 11 and 12: “epitope-binding” should read “epitope binding”.
Appropriate correction is required.
Claim Interpretation
Claims 1, 11, 12, and 20 recite the transitional phrase “having”, the scope of which is not defined by the specification. As such, according to MPEP 2111.03(IV), the term will be interpreted as an open-ended transitional term, similar to the transitional phrase “comprising”. For example, the structure recited in the claims can comprise additional, unrecited elements.
Further, Examiner acknowledges that the term “pro-AREG” refers to the 252 amino acid transmembrane precursor of the AREG protein comprising SEQ ID NO: 135 (see para. [090]).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 21 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 21 is drawn to the isolated AREG protein of claim 20, which is an epitope for producing the anti-AREG antibody or fragment wherein the AREG antibody or fragment has the ability of inhibiting fibrosis, preferably, the fibrosis is renal fibrosis, hepatic fibrosis, pulmonary fibrosis, more preferably, IPF. Claim 21 does not further limit the subject matter of claim 20 because it recites an intended use which does not disclose a fundamental characteristic of the claimed invention that is properly construed as a limitation of the claim (see MPEP 2111.02(II)).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-13, 17, and 20-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The terms “preferably” and “more preferably” in claims 1-5, 7, 13, and 21 render the claims indefinite because it is unclear whether the limitations following the term are part of the claimed invention. See MPEP § 2173.05(d). As such, claims 1-5, 7, 13, 21, and their dependent claims, are rejected.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “fibrosis”, and the claim also recites “renal fibrosis, hepatic fibrosis, pulmonary fibrosis… IPF” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 2 recites the broad recitation “AREG”, and the claim also recites “human AREG” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3 recites the broad recitation “a human anti-AREG antibody, or a murine anti-AREG antibody, or a humanized anti-AREG antibody, or a chimeric anti-AREG antibody”, and the claim also recites “human monoclonal antibody (mAb), murine mAb, humanized mAb, or chimeric mAb” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The term “high affinity” in claim 4 is a relative term which renders the claim indefinite. The term “high affinity” 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. The claims nor the specification provide a definition for one to understand what the term encompasses or what is considered to be “high affinity” without a standard value to compare. Therefore, one would not be apprised of the scope of the invention.
The term “about” in claim 4 renders the claim scope indefinite. In determining the range encompassed by the term "about" , one must consider the context of the term as it is used in the specification and claims of the application. Ortho-McNeil Pharm., Inc. v. Caraco Pharm. Labs., Ltd., 476 F.3d 1321, 1326, 81 USPQ2d 1427, 1432 (Fed. Cir. 2007). There is nothing in the specification, prosecution history, or the prior art to provide any indication as to what range of specific activity is covered by the term "about." See MPEP 2173.05(b)(III)(A) and Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991). Particularly, the specification recites the term “about” generally means an acceptable degree of error for the quantity measured given the nature or precision of the measurements (see [093]), thus one would not be apprised as to what is encompassed by the term because the specification fails to provide a standard for ascertaining the requisite degree.
Further, claim 4 recites the language “less than about” which renders the claim indefinite because the phrase requires a minimum and variability. It is impossible to have both a minimum and variability in a threshold.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 4 recites the broad recitation “less than about 10nM” and “1x10-8-1x10-11 ”, and the claim also recites “less than 1 nM, 0.1 nM, or 0.01 nM” and “1x10-9 - 1x10-11“, respectively, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 5 recites the broad recitation “soluble forms of AREG”, and the claim also recites “EGF-like domain of soluble forms of AREG” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 6 recites the limitation "the human pro-AREG” and “the murine pro-AREG" in lines 2-4. There is insufficient antecedent basis for this limitation in the claim.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 6 recites the broad recitation “residues 101-184 of the human pro-AREG” and “residues 94-177 of the murine pro-AREG”, and the claim also recites “171-184 of the human pro-AREG” and “135-177 of the murine pro-AREG”, respectively, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Further, claim 6 recites “and/or” which renders the claim indefinite because the phrase introduces alternate amino acid residues that also overlap in scope.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 7, 9, and 10 recite the broad recitation “at least…one”, and the claims also recite “at least… two, three, four or five” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 recites the broad recitation “within residues 101-184 of pro-AREG”, and the claim also recites “within residues 142-184 of human pro-AREG” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 7, 9, 10, and 20 recite “shown by … SEQ ID NO: XXX”. The language is indefinite because it is unclear if the amino acid is limited to the full sequence of the SEQ ID NO, or the amino acid sequence can be of any length as long as the SEQ ID NO is within the sequence. The term “an amino acid sequence” could refer to any two amino acids joined by a peptide bond that appears within the sequence of SEQ ID NO: 123. Further, it is unclear if the language of the claim requires an open configuration similar to “comprising” or a closed configuration similar to “consisting of”. As such, claims 7, 9, 10, 20, and their dependent claims, are rejected.
Claim 8 recites “Glu149 and/or His164”, however, there is no base sequence to compare the residues.
Claims 9 and 10 recite “the combinations thereof”. It is unclear if Applicant is referring to the combinations of CDRs recited, or if Applicant is referring to a combination of amino acid additions, deletions, or conservative amino acid substitutions. If the latter, the examiner suggests amending the language to recite “a combination thereof” to overcome the rejection.
Further, claims 9 and 10 recites the limitation "the combinations thereof". There is insufficient antecedent basis for this limitation in the claim.
The language “one, two, three, four, or five amino acids addition, deletion, conservative amino acid substitution…” in claims 9 and 10 renders the claims indefinite because the scope of the encompassed substitutions is indefinite.
Claim 11 recites the limitation "the amino acid sequence" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Further, it is unclear if Applicant is claiming two different peptides in claim 11, or just one, with the 100% and 95% as alternatives.
The term “retaining the activity of epitope-binding” in claims 11 and 12 is a relative term which renders the claim indefinite. The term “retaining the activity of epitope-binding” 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. The claims nor the specification disclose which amino acid residues must be conserved in order to “retain the activity of epitope-binding”. Additionally, the claims do not provide a standard or a control for one to compare; thus, one would not be apprised as to what is considered “retaining the activity of epitope-binding”. As such, claims 11 and 12 are rejected.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 recites the broad recitation “IgG”, and the claim also recites “IgG1, IgG2, IgG3, or IgG4” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 20 recites “an amino acid sequence”. This language is indefinite because it is unclear if the language requires the entire sequence of the SEQ ID NO, or if any two amino acids in sequence is the only requirement. As such, claim 20 and its dependent claims are rejected.
Claim 21 is drawn to the isolated AREG protein of claim 20, which is an epitope for producing the anti-AREG antibody or fragment wherein the AREG antibody or fragment has the ability of inhibiting fibrosis, preferably, the fibrosis is renal fibrosis, hepatic fibrosis, pulmonary fibrosis, more preferably, IPF. This is indefinite because the limitation indicates a method step; therefore, one would not understand whether Applicant is claiming a composition or a method of producing an anti-AREG antibody or fragment thereof.
Claim 21 recites the limitation "the anti-AREG antibody or fragment" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 21 recites the term “fragment”. It is unclear if the term is in reference to the anti-AREG antibody, or if the term is in reference to the isolated AREG protein. If the former, the examiner suggests amending the language to recite “fragment thereof”.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-13, 17, and 20-22 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making 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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to an isolated anti-AREG antibody or fragment thereof, having the ability of inhibiting fibrosis, preferably, the fibrosis is renal fibrosis, hepatic fibrosis, pulmonary fibrosis, more preferably, IPF.
Claim 2 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which is capable of binding to AREG, preferably, binding to human AREG.
Claim 3 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which is a human anti- AREG antibody, or a murine anti-AREG antibody, or a humanized anti-AREG antibody, or a chimeric anti-AREG antibody, preferably, is a human monoclonal antibody (mAb), murine mAb, humanized mAb, or chimeric mAb, or which preferably is Fab fragment or F(ab)2 fragment.
Claim 4 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which binds to AREG with high affinity, preferably, with a dissociation constant (KD) of less than about 10 nM, preferably, less than 1 nM, 0.1 nM, or 0.01 nM, preferably, in the range of 1x10-8- 1x10-11, more preferably, in the range of 1x10-9- 1x10-11.
Claim 5 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which is capable of binding to soluble forms of AREG, preferably, is capable of binding to EGF-like domain of soluble forms of AREG.
Claim 6 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which is capable of binding to residues 101-184 of the human pro-AREG, and/or residues 171-184 of the human pro-AREG, and/or residues 94-177 of the murine pro-AREG, and/or residues 135-177 of the murine pro-AREG.
Claim 7 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which is capable of binding at least one, two, three, four or five amino acids within residues 101-184 of pro-AREG shown by any one of SEQ ID NOs: 123-132, preferably, within residues 142-184 of human pro- AREG shown by any one of SEQ ID NOs: 123-132.
Claim 8 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which is capable of interacting with Glu149 and/or His164 of human pro-AREG.
Claim 9 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which comprises a heavy chain variable region comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein: HCDR1, HCDR2, and HCDR3 are selected from the group consisting of:(1) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 2, HCDR3 shown by SEQ ID NO: 3;(2) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 2, HCDR3 shown by SEQ ID NO: 4; (3) HCDR1 shown by SEQ ID NO: 5, HCDR2 shown by SEQ ID NO: 2, HCDR3 shown by SEQ ID NO: 6; (4) HCDR1 shown by SEQ ID NO: 7, HCDR2 shown by SEQ ID NO: 8, HCDR3 shown by SEQ ID NO: 9; (5) HCDR1 shown by SEQ ID NO: 7, HCDR2 shown by SEQ ID NO: 10, HCDR3 shown by SEQ ID NO: 9; (6) HCDR1 shown by SEQ ID NO: 7, HCDR2 shown by SEQ ID NO: 8, HCDR3 shown by SEQ ID NO: 11; (7) HCDR1 shown by SEQ ID NO: 7, HCDR2 shown by SEQ ID NO: 8, HCDR3 shown by SEQ ID NO: 12;(8) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 13, HCDR3 shown by SEQ ID NO: 14;(9) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 15, HCDR3 shown by SEQ ID NO: 16;(10) HCDR1 shown by SEQ ID NO: 17, HCDR2 shown by SEQ ID NO: 18, HCDR3 shown by SEQ ID NO: 19;(11) HCDR1 shown by SEQ ID NO: 17, HCDR2 shown by SEQ ID NO: 18, HCDR3 shown by SEQ ID NO: 20;(12) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 13, HCDR3 shown by SEQ ID NO: 136; and(13) HCDR1, HCDR2, HCDR3 as shown in (1)-(12), but at least one of which includes one, two, three, four or five amino acids addition, deletion, conservative amino acid substitution or the combinations thereof; andLCDR1, LCDR2, and LCDR3 are selected from the group consisting of:(1) LCDR1 shown by SEQ ID NO: 21, LCDR2 shown by SEQ ID NO: 22, LCDR3 shown by SEQ ID NO: 23;(2) LCDR1 shown by SEQ ID NO: 21, LCDR2 shown by SEQ ID NO: 22, LCDR3 shown by SEQ ID NO: 24;(3) LCDR1 shown by SEQ ID NO: 25, LCDR2 shown by SEQ ID NO: 26, LCDR3 shown by SEQ ID NO: 27;(4) LCDR1 shown by SEQ ID NO: 28, LCDR2 shown by SEQ ID NO: 29, LCDR3 shown by SEQ ID NO: 30;(5) LCDR1 shown by SEQ ID NO: 31, LCDR2 shown by SEQ ID NO: 32, LCDR3 shown by SEQ ID NO: 30;(6) LCDR1 shown by SEQ ID NO: 33, LCDR2 shown by SEQ ID NO: 34, LCDR3 shown by SEQ ID NO: 30;(7) LCDR1 shown by SEQ ID NO: 35, LCDR2 shown by SEQ ID NO: 34, LCDR3 shown by SEQ ID NO: 30;(8) LCDR1 shown by SEQ ID NO: 36, LCDR2 shown by SEQ ID NO: 37, LCDR3 shown by SEQ ID NO: 38;Response to Office Action of August 22, 2025 (9) LCDR1 shown by SEQ ID NO: 39, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 38;(10) LCDR1 shown by SEQ ID NO: 41, LCDR2 shown by SEQ ID NO: 42, LCDR3 shown by SEQ ID NO: 38;(11) LCDR1 shown by SEQ ID NO: 43, LCDR2 shown by SEQ ID NO: 44, LCDR3 shown by SEQ ID NO: 38;(12) LCDR1 shown by SEQ ID NO: 39, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 38;(13) LCDR1 shown by SEQ ID NO: 45, LCDR2 shown by SEQ ID NO: 42, LCDR3 shown by SEQ ID NO: 46;(14) LCDR1 shown by SEQ ID NO: 47, LCDR2 shown by SEQ ID NO: 44, LCDR3 shown by SEQ ID NO: 46;(15) LCDR1 shown by SEQ ID NO: 48, LCDR2 shown by SEQ ID NO: 37, LCDR3 shown by SEQ ID NO: 49;(16) LCDR1 shown by SEQ ID NO: 50, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 51;(17) LCDR1 shown by SEQ ID NO: 50, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 52;(18) LCDR1 shown by SEQ ID NO: 50, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 53;(19) LCDR1 shown by SEQ ID NO: 54, LCDR2 shown by SEQ ID NO: 42, LCDR3 shown by SEQ ID NO: 55;(20) LCDR1 shown by SEQ ID NO: 56, LCDR2 shown by SEQ ID NO: 44, LCDR3 shown by SEQ ID NO: 55; and(21) LCDR1, LCDR2, LCDR3 as shown in (1)-(20), but at least one of which includes one, two, three, four or five amino acids addition, deletion, conservative amino acid substitution or the combinations thereof.
Claim 10 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which comprises a heavy chain variable region comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are selected from the group consisting of: (1) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 2, HCDR3 shown by SEQ ID NO: 3, LCDR1 shown by SEQ ID NO: 21, LCDR2 shown by SEQ ID NO: 22, LCDR3 shown by SEQ ID NO: 23; (2) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 2, HCDR3 shown by SEQ ID NO: 4, LCDR1 shown by SEQ ID NO: 21, LCDR2 shown by SEQ ID NO: 22, LCDR3 shown by SEQ ID NO: 24; (3) HCDR1 shown by SEQ ID NO: 5, HCDR2 shown by SEQ ID NO: 2, HCDR3 shown by SEQ ID NO: 6, LCDR1 shown by SEQ ID NO: 25, LCDR2 shown by SEQ ID NO: 26, LCDR3 shown by SEQ ID NO: 27; (4) HCDR1 shown by SEQ ID NO: 7, HCDR2 shown by SEQ ID NO: 8, HCDR3 shown by SEQ ID NO: 9, LCDR1 shown by SEQ ID NO: 28, LCDR2 shown by SEQ ID NO: 29, LCDR3 shown by SEQ ID NO: 30; (5) HCDR1 shown by SEQ ID NO: 7, HCDR2 shown by SEQ ID NO: 10, HCDR3 shown by SEQ ID NO: 9, LCDR1 shown by SEQ ID NO: 31, LCDR2 shown by SEQ ID NO: 32, LCDR3 shown by SEQ ID NO: 30; (6) HCDR1 shown by SEQ ID NO: 7, HCDR2 shown by SEQ ID NO: 8, HCDR3 shown by SEQ ID NO: 11, LCDR1 shown by SEQ ID NO: 33, LCDR2 shown by SEQ ID NO: 34, LCDR3 shown by SEQ ID NO: 30; (7) HCDR1 shown by SEQ ID NO: 7, HCDR2 shown by SEQ ID NO: 8, HCDR3 shown by SEQ ID NO: 12, LCDR1 shown by SEQ ID NO: 35, LCDR2 shown by SEQ ID NO: 34, LCDR3 shown by SEQ ID NO: 30; (8) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 13, HCDR3 shown by SEQ ID NO: 14, LCDR1 shown by SEQ ID NO: 36, LCDR2 shown by SEQ ID NO: 37, LCDR3 shown by SEQ ID NO: 38;(9) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 13, HCDR3 shown by SEQ ID NO: 136, LCDR1 shown by SEQ ID NO: 39, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 38;(10) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 13, HCDR3 shown by SEQ ID NO: 136, LCDR1 shown by SEQ ID NO: 41, LCDR2 shown by SEQ ID NO: 42, LCDR3 shown by SEQ ID NO: 38;(11) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 13, HCDR3 shown by SEQ ID NO: 136, LCDR1 shown by SEQ ID NO: 43, LCDR2 shown by SEQ ID NO: 44, LCDR3 shown by SEQ ID NO: 38;(12) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 15, HCDR3 shown by SEQ ID NO: 16, LCDR1 shown by SEQ ID NO: 39, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 38;(13) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 15, HCDR3 shown by SEQ ID NO: 16, LCDR1 shown by SEQ ID NO: 45, LCDR2 shown by SEQ ID NO: 42, LCDR3 shown by SEQ ID NO: 46;(14) HCDR1 shown by SEQ ID NO: 1, HCDR2 shown by SEQ ID NO: 15, HCDR3 shown by SEQ ID NO: 16, LCDR1 shown by SEQ ID NO: 47, LCDR2 shown by SEQ ID NO: 44, LCDR3 SHOWN BY SEQ ID NO: 46;(15) HCDR1 shown by SEQ ID NO: 17, HCDR2 shown by SEQ ID NO: 18, HCDR3 shown by SEQ ID NO: 19, LCDR1 shown by SEQ ID NO: 48, LCDR2 shown by SEQ ID NO: 37, LCDR3 shown by SEQ ID NO: 49;(16) HCDR1 shown by SEQ ID NO: 17, HCDR2 shown by SEQ ID NO: 18, HCDR3 shown by SEQ ID NO: 20, LCDR1 shown by SEQ ID NO: 50, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 51;(17) HCDR1 shown by SEQ ID NO: 17, HCDR2 shown by SEQ ID NO: 18, HCDR3 shown by SEQ ID NO: 20, LCDR1 shown by SEQ ID NO: 50, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 52;(18) HCDR1 shown by SEQ ID NO: 17, HCDR2 shown by SEQ ID NO: 18, HCDR3 shown by SEQ ID NO: 20, LCDR1 shown by SEQ ID NO: 50, LCDR2 shown by SEQ ID NO: 40, LCDR3 shown by SEQ ID NO: 53;(19) HCDR1 shown by SEQ ID NO: 17, HCDR2 shown by SEQ ID NO: 18, HCDR3 shown by SEQ ID NO: 20, LCDR1 shown by SEQ ID NO: 54, LCDR2 shown by SEQ ID NO: 42, LCDR3 shown by SEQ ID NO: 55;(20) HCDR1 shown by SEQ ID NO: 17, HCDR2 shown by SEQ ID NO: 18, HCDR3 shown by SEQ ID NO: 20, LCDR1 shown by SEQ ID NO: 56, LCDR2 shown by SEQ ID NO: 44, LCDR3 shown by SEQ ID NO: 55; and(21) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3 as shown in (1)-(20), but at least one of which includes one, two, three, four or five amino acids addition, deletion, conservative amino acid substitution or the combinations thereof.
Claim 11 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which comprises a heavy chain variable region, and a light chain variable region, wherein the heavy chain variable region has the amino acid sequence selected from the group consisting of SEQ ID NOs: 57-69, and an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 57- 69, and retaining the activity of epitope-binding, wherein the light chain variable region has the amino acid sequence selected from the group consisting of SEQ ID NOs: 70-89, and an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 70-89, and retaining the activity of epitope-binding.
Claim 12 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which comprises a heavy chain variable region, and a light chain variable region, wherein the heavy chain variable region and the light chain variable region have the amino acid sequences selected from the group consisting of: (1) SEQ ID NO: 57 and SEQ ID NO: 70; (2) SEQ ID NO: 58 and SEQ ID NO: 71; (3) SEQ ID NO: 59 and SEQ ID NO: 72; (4) SEQ ID NO: 60 and SEQ ID NO: 73; (5) SEQ ID NO: 61 and SEQ ID NO: 74; (6) SEQ ID NO: 62 and SEQ ID NO: 75; (7) SEQ ID NO: 63 and SEQ ID NO: 76;Response to Office Action of August 22, 2025 (8) SEQ ID NO: 64 and SEQ ID NO: 77;(9) SEQ ID NO: 65 and SEQ ID NO: 78;(10) SEQ ID NO: 66 and SEQ ID NO: 79;(11) SEQ ID NO: 66 and SEQ ID NO: 80;(12) SEQ ID NO: 66 and SEQ ID NO: 81;(13) SEQ ID NO: 67 and SEQ ID NO: 79;(14) SEQ ID NO: 67 and SEQ ID NO: 82;(15) SEQ ID NO: 67 and SEQ ID NO: 83;(16) SEQ ID NO: 68 and SEQ ID NO: 84;(17) SEQ ID NO: 69 and SEQ ID NO: 85;(18) SEQ ID NO: 69 and SEQ ID NO: 86;(19) SEQ ID NO: 69 and SEQ ID NO: 87;(20) SEQ ID NO: 69 and SEQ ID NO: 88;(21) SEQ ID NO: 69 and SEQ ID NO: 89; and (22) two amino acid sequences having at least 95% sequence identity to any one of (1)-(21) respectively, and retaining the activity of epitope-binding.
Claim 13 is drawn to the anti-AREG antibody or fragment thereof of claim 1, which is an isotype of IgG, IgM, IgA, IgE or IgD, preferably, an isotype of IgG1, IgG2, IgG3, or IgG4.
Claim 17 is drawn to a composition comprising the anti-AREG antibody or fragment thereof according to claim 1, and a pharmaceutical acceptable carrier.
Claim 20 is drawn to an isolated AREG protein, having an amino acid sequence shown in any one of SEQ ID NOs: 123-132, or an amino acid sequence that is at least 85% identical to any one of SEQ ID NOs: 123-132.
Claim 21 is drawn to the isolated AREG protein of claim 20, which is an epitope for producing the anti-AREG antibody or fragment wherein the AREG antibody or fragment has the ability inhibiting fibrosis, preferably, the fibrosis is renal fibrosis, hepatic fibrosis, pulmonary fibrosis, more preferably, IPF.
Claim 22 is drawn to the isolated AREG protein of claim 20, which has the amino acid Glu149 and/or His164.
The specification discloses the generation of human monoclonal antibodies (mAbs) against AREG from a phage library (see Example 1). Specifically, the specification discloses of improving the affinity of E1L2 antibody comprising engineering the VH-CDR3 and VL-CDR3 (see [0153]). Further, the VL CDRs were grafted to human IGLV1-44*01 germline to improve solubility (see [0153]). The phage library identified six anti-AREG human mAbs wherein two of the six (i.e., E1L2 and P7) were selected for further characterization based on their binding specificity and affinity to both human and mouse AREG (see [0158], and Tables 1-2). The E1H3L4 antibody, comprising three amino acid changes in the VH-CDR3 and four amino acid changes in the VL-CDR3 compared to E1L2, showed slightly stronger binding to mAREG than P7 (see [0164]).
Further, the specification discloses the generation of mAbs against AREG using mouse hybridoma method and humanization of the mouse mAbs (see Example 2). Human AREG EGF-like domain fused with an Fc fragment of human IgG1 or mouse IgG2a was expressed in 293F as a fusion protein, named as hAREG-EGFd-hFc and hAREG-EGFd-mFc, respectively (see [0167]). For humanization of the AREG mAbs, sequences of murine mAbs were searched for human germline IgG genes homologous to identify the human germline genes with high homology to the murine mAbs (9C12, 23H8 and 1H9), and then chosen them as templates for humanization (see [0172]). To improve the affinity of the hu9C12v1 antibody, two phage display sub-libraries with random mutagenesis for the HCDR3 and LCDR1 were constructed through NNK degenerate codons; only hits with higher affinities than hu9C12v1 were retained after the screening (see [0174]).
Lastly, the specification discloses that the E1H3L4, P7 and hu9C12v4 all competed with mAREG-DLLA for binding to mEGFR-ECD, with hu9C12v4 showing the best activity among the three mAbs (see [0209]). hu9C12v4, hu9C12v6, hu23H8v5, hu23H8v6 and hu1H9v3 in their hIgG1 forms all showed potent activity in competition with hAREG-DLLA for binding to hEGFR-ECD with subnanomolar IC50 (see [0209]). 1.2 nM of 23H8 or 1H9 completely blocked hAREG-induced phosphorylation of EGFR, whereas 9C12 showed relatively weaker blocking activity (see [0212]). To identify the epitopes of our anti-AREG mAbs, five hAREG-EGFd variants were generated by changing each amino acid at five different sites of hAREG-EGFd to the counterpart amino acid of mAREG-EGFd (see Figure 3; [0214]). Two amino acids (Glu149 and His164) were identified as critical epitope residues for the binding of the mAb to hAREG; for hu9C12v4, hu9C12v6, hu23H8 and hu1H9 mAbs, the hAREG-H164N variant completely lost binding activity to mAbs, hAREG-E164K variant had slightly reduced binding activity, and other three hAREG variants had no effect on the binding of the mAbs, demonstrating that His164 is the most critical epitope residue for the binding of our anti-AREG mAbs (see [0214]). The specification found that anti-AREG antibodies P7, E1H3L4, and hu9C12v4 prolonged survival time of Cdc42 AT2 null mice (see [0239]-[0243]).
However, the specification fails to disclose that Applicant was in possession of the large genus of anti-AREG antibodies or fragments thereof as claimed. Specifically, the specification fails to disclose that Applicant was in possession of the genus of antibodies wherein at least one CDR comprises at least one, two, three, four, or five amino acid modifications as described in claims 9 and 10; or, variable heavy and light chains comprising at least 95% identity with the sequences recited in claims 11 and 12. Lastly, the specification fails to disclose which sequences must be conserved of the isolated AREG protein in order to produce an anti-AREG protein.
Although the specification discloses several species of anti-AREG antibodies (see Tables 1-4, 7-8, and 11-12), the claims are not limited to these inhibitors, and are inclusive of any isolated anti-AREG antibody or fragments thereof. This indicates that there are hundreds, if not thousands, of possible anti-AREG antibodies or fragments thereof encompassed by the claims. Thus, the claims encompass a vast genus of antibodies that have the claimed functions. However, the specification provides limited guidance on the structure required for maintaining the claimed function(s). Therefore, the specification does not provide adequate written description to identify the broad and variable genus of anti-AREG antibodies or fragments thereof because, inter alia, the specification does not disclose a correlation between the necessary structure of the inhibitor and the function(s) recited in the claims; and 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 the members of the genus, because while the description of an ability of the claimed substance may generically describe the molecule’s function, it does not describe the substance itself. A definition by function does not suffice to define the genus because it is only an indication of what the substance does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of substances is highly variable (i.e. each substance would necessarily have a unique structure, See MPEP 2434), the generic description of the substance 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 and variants thereof claimed only be a functional characteristic(s) and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
MPEP § 2163.03(V) states:
While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976), a question as to whether a specification provides an adequate written description may arise in the context of an original claim. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. “Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Applicant has not shown possession of a representative number of species of anti-AREG antibodies or fragments thereof, and AREG proteins. 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]." 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.") (MPEP 2163).
The instant claims do not fully describe the structure of the anti-AREG antibodies and AREG proteins to achieve the required function. Accordingly, the specification also does not provide adequate written description to identify the broad genus of anti-AREG antibodies or fragments thereof, or AREG proteins, claimed only by a function characteristic(s) 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 anti-AREG antibodies or fragments thereof, and AREG proteins had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of anti-AREG antibodies or fragments thereof, and AREG proteins claimed only by a partial structure and functional characteristic(s). Thus the anti-AREG antibodies or fragments thereof, and AREG proteins described by the instant claims encompasses an overly broad genus, and the functional outcome.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, 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 of anti-AREG antibodies by the functions of having the ability of inhibiting fibrosis and binding to AREG. Additionally, the claims attempt to define the genus of AREG proteins by the ability to produce anti-AREG antibodies. 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.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
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.)
Further, the skilled artisan cannot envision the detailed chemical structure of the encompassed anti-AREG antibodies or fragments thereof, or AREG proteins, 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.
Regarding the encompassed antibodies, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. 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. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches 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." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of possible antibodies and variants thereof that have specific required functions. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) as taught by Skolnick et al. (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence-based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cell (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). Additionally, Bork (Genome Research, 2000,10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the functional proteins that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides that may be encompassed by the instant claims (see e.g. page 661, left column).
The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column).
Given not only the teachings of Skolnick et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed anti-AREG antibodies or fragments thereof could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner.
Further, the instant claims are directed to the anti-AREG antibodies or fragments thereof retaining the activity of epitope binding. The claim limitation does not require that the “fragment thereof” possess any particular distinguishing feature or conserved structure, but only that it “retains the activity of epitope binding”, which encompasses any domain of the AREG protein, and of all fragments and variants comprising any sequence comprising any size of the AREG. It is the examiner’s position that the disclosure of the instant application does not convey applicant’s possession of the claimed genus of “fragment thereof” from anti-AREG antibodies.
As stated above, the specification discloses the reduction to practice of only the full-length antibody species (see Tables 1-4, 7-8, and 11-12) within the claimed genus. These polypeptides, however, do not reflect the structures of the epitopes or immunogenic fragments/antigens within each polypeptide sequence. Consequently, there is no information about which and how many amino acids are required for raising an immune response.
There is no disclosure relating similarity of any partial structure of anti-AREG antibodies to conservation of the immunogenic function. It is known for proteins, albeit not in all cases, that amino acid addition(s), substitution(s) or deletion(s) can destroy the function of the epitope or abolish its ability. This lack of predictability of the relationship between the protein sequence and the immunogenic epitope function is well documented by Mateu et al. (Mateu MG, et. al. Eur J Immunol. 1992 Jun;22(6):1385-9.) and Greenspan et al. (Greenspan NS, Di Cera E. Defining epitopes: It's not as easy as it seems. Nat Biotechnol. 1999 Oct;17(10):936-7.). The effects of these changes are largely unpredictable as to which ones have a significant effect versus not. Thus, the specification fails to adequately describe at least a substantial number of members of the immunogenic fragment genus to which the claims are based.
In summary, there are no known or disclosed antibody fragments having immunogenic activity other than the full-length polypeptides. As of the filing date, there was no known or disclosed correlation between a partial structure and immunogenic activity. Accordingly, one of skill in the art would not accept the disclosure of the full-length antibody as representative of fragments, homologs, or variants having immunogenic activity. Based on the lack of knowledge and predictability in the art, those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of immunogenic fragments based on the disclosure of the instant application.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of proteins, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited dissociation constant, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all anti-AREG antibodies or fragments thereof.
A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies.
While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the claimed anti-AREG antibodies or fragments thereof, and AREG proteins. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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).
Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of anti-AREG antibodies or fragments thereof, and AREG proteins as claimed. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
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.
Landolfi
Claims 1-5, 13, 17, and 20-22 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Landolfi et al (WO 2004/068931 A2, publication date: 08/19/2004).
With respect to instant claims 1-3, and 5, Landolfi et al disclose of anti-amphiregulin (AR or AREG) antibodies, preferably humanized monoclonal antibodies (see Abstract). Particularly, Landolfi et al disclose that the anti-AR antibody is capable of binding to an amino acid sequence having at least 80% homology to an AR amino acid sequence such as the human AR amino acid sequence (SEQ ID NO: 1; see page 5, lines 22-24). Additionally, Landolfi et al disclose of antibody PAR34 binds to soluble AR (see Fig. 18 and page 9, lines 6-10). Landolfi et al discloses that the antibodies were capable of binding to AR expressed on the cells surface (see Figure 2).
Further, while the antibodies of Landolfi et al are directed to treating cancer and psoriasis (see Abstract; Examples 4, 5, 8 and 9), Landolfi et al disclose the antibodies bind to the specific epitope (i.e., AREG); thus, it is inherent that the antibodies of Landolfi et al will have the ability to inhibit fibrosis.
With respect to instant claim 4, Landolfi et al disclose that the antibodies PAR34 and HuPAR34 bind to AR with high affinity with a dissociation constant of 0.41±0.082 nM and 0.53±0.050 nM, respectively (see Example 6 and Table 2).
With respect to instant claim 13, Landolfi et al disclose that the anti-AR antibodies can have all types of constant regions including IgM, IgG, IgD, IgA, and IgE, and any isotype, including IgG1, IgG2a, IgG2b, IgG3 and IgG4 (see page 24, lines 6-8),
With respect to instant claim 17, Landolfi et al disclose that the anti-AR antibodies can be formulated as a pharmaceutical composition comprising the antibody and a pharmaceutical acceptable carrier (see Abstract; page 5, lines 1-4).
Lastly, with respect to instant claims 20-22, Landolfi et al disclose of the human AR amino acid sequence comprising SEQ ID NO: 1 (see page 21, lines 5-17). This sequence comprises both Glu149 and His164 (see page 21, lines 14 and 15), as well as the sequences recited in claim 20 (see example alignment below). Landolfi et al also disclose that the functionally active AR fragments or derivatives can be produced to share a certain degree of sequence identity or sequence similarity with SEQ ID NO: 1 (see page 21, lines 19-32). Landolfi et al disclose that a recombinant human AR was used to generate the anti-AR monoclonal antibodies (See Example 2).
Instant SEQ ID NO: 132 Alignment
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As such, the teachings of Landolfi et al anticipate the present invention.
Caswell
Claims 1-8, 17, and 20-22 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Caswell et al (WO 2009/127881 A1, publication date: 10/22/2009).
With respect to instant claims 1-3 and 5, Caswell et al disclose of antibody molecules with binding specificity for both AREG and HBEGF (see Abstract). Caswell et al disclose that the antibody molecules can be a Fab fragment or F(ab)2 fragment (see page 30, lines 5-26), or a chimeric antibody (see page 32, lines 30 and 31; page 33, lines 1-18).
While the antibody molecules of Caswell et al are directed to treating cancer and diseases associated with angiogenesis (see Abstract), Caswell et al establishes that the antibody molecules bind to the specific epitope (i.e., AREG); thus, it is inherent that the antibody molecules of Caswell et al will have the ability to inhibit fibrosis.
With respect to instant claim 4, Caswell et al disclose that the claimed antibody molecules have an affinity of at least 10-7 M (see page 4, lines 25-28; page 12, lines 14-18).
With respect to instant claims 6-8 and 20-22, Caswell et al disclose that the claimed antibody molecules bind to an antigenic fragment of AREG having the amino acid sequence shown as Sequence ID NO: 1 (see page 6, lines 9-19). This sequence corresponds to residues 142-185 of the human AREG protein (see Fig. 5). Further, Sequence ID No: 1 shares 100% identity with instant SEQ ID NO: 123 (see alignment below). Lastly, the AREG sequence shown in Figure 5 comprises Glu149 and His164.
SEQ ID NO: 132 Alignment
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Lastly, with respect to instant claim 17, Caswell et al disclose that the claimed antibody molecules can be formulated into a pharmaceutical composition comprising the claimed antibody molecule and a pharmaceutical acceptable carrier (see page 45, lines 23-31).
As such, the teachings of Caswell et al anticipate the present invention.
Yarden
Claims 1-8, 17, and 20-22 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Yarden et al (WO 2016/147194A1, publication date: 09/22/2016).
With respect to instant claims 1-3 and 5, Yarden et al disclose of anti-amphiregulin (AREG) antibodies, compositions comprising the same and uses thereof (see Title). Yarden et al disclose that that the claimed anti-AREG antibodies can be humanized or chimeric (see page 5, lines 22-24; page 31, lines 11-32). Yarden et al disclose that the pro-AREG protein is a soluble protein (see page 2, lines 1-6).
While the antibodies of Yarden et al are directed to treating cancer (see Abstract), Yarden et al establishes that the antibodies bind to the specific epitope (i.e., AREG); thus, it is inherent that the antibodies of Yarden et al will have the ability to inhibit fibrosis.
With respect to instant claim 4, Yarden et al disclose that the claimed antibodies bind to human AREG with high affinity; specifically, less than 10 nM (see Table 3; page 37, lines 7-10).
With respect to instant claims 6-8 and 20-22, Yarden et al disclose that anti-AREG antibodies were generated by immunizing a human AREG protein or peptide thereof (e.g. AREG’s EGF-like domain SEQ ID NO: 91) to produce an antibody response against the AREG protein or peptide thereof (see page 34, lines 8-15). SEQ ID NO: 92 (the amino acid of SEQ ID NO: 91) of Yarden et al shares 100% identity with instant SEQ ID NO: 123 (see alignment below). This sequence also corresponds to residues 101-198 of the human AREG protein (see Fig. 5). Lastly, the AREG sequence comprises Glu149 and His164.
SEQ ID NO: 123 Alignment
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Lastly, with respect to instant claim 17, Yarden et al disclose that the claimed antibodies can be formulated as a pharmaceutical composition comprising as an active ingredient the antibody of the invention and a pharmaceutically acceptable carrier (see page 6, lines 13-16; claim 30).
As such, the teachings of Yarden et al anticipate the present invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
18/688,572
Claims 1-8, 13, 17, and 20-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7-10, 15, 18-20, 22, 25-26, 33, and 35-36 of copending Application No. 18/688,572 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘572 application is drawn to a bi-functional fusion protein comprising a first domain and a second domain, wherein the first domain is capable of binding to AREG or a fragment thereof, preferably is an antibody or an antigen-binding fragment thereof that binds to AREG or a fragment thereof, and the second domain is capable of binding to a TGF ligand or a fragment thereof, preferably comprises a part of the ectodomain of TGFO receptor II (TRII) or a variant thereof (see claim 1).
The ‘572 application is drawn to the bi-functional protein of claim 1, wherein the antibody or the antigen-binding fragment thereof, binding to both human AREG and mouse AREG, alternatively, the anti-AREG antibody or the fragment thereof is capable of binding to human AREG with weak or without cross-reactivity to mouse AREG, and/or wherein the anti-AREG antibody or the fragment thereof is a human anti-AREG antibody, a murine anti-AREG antibody, a chimeric anti-AREG antibody, or a humanized anti-AREG antibody, preferably, is a human monoclonal antibody (mAb), murine mAb, chimeric mAb or humanized mAb, and/or wherein the anti-AREG antibody or the fragment thereof is capable of binding to a soluble form of AREG, preferably, is capable of binding to an epidermal growth factor (EGF)-like domain of the soluble form of AREG, and/or wherein the anti-AREG antibody or the fragment thereof is an isotype of IgG, IgM, IgA, IgE, IgD or a variant thereof, preferably, an isotype of IgG1, IgG2, IgG3, IgG4 or a variant thereof (see claim 4).
The ’572 application is drawn to the bi-functional fusion protein of claim 1, wherein the anti- AREG antibody or the fragment thereof comprises a heavy chain variable region comprising heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising light chain complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein:HCDR1, HCDR2, and HCDR3 are selected from a group consisting of: (1) HCDR1: SYAMS (SEQ ID NO: 1), HCDR2: AISGSGGSTYYADSVKG (SEQ ID NO: 2), HCDR3: PTSRYSYGYDY (SEQ ID NO: 3);(2) HCDR1: SYAMS (SEQ ID NO: 1), HCDR2: AISGSGGSTYYADSVKG (SEQ ID NO: 2), HCDR3: PTSRYSYSYNN (SEQ ID NO: 4);(3) HCDR1: SHAMS (SEQ ID NO: 5), HCDR2: AISGSGGSTYYADSVKG (SEQ ID NO: 2), HCDR3: VDTKFDP (SEQ ID NO: 6);(4) HCDR1: SYPMS (SEQ ID NO: 7), HCDR2: TISTGGTYTYYPDSVKG (SEQ ID NO: 8), HCDR3: QGPIYYGNYYYAMDY (SEQ ID NO: 9);(5) HCDR1: SYPMS (SEQ ID NO: 7), HCDR2: TISTGGRYTYYPDSVKG (SEQ ID NO: 10), HCDR3: QGPIYYGNYYYAMDY (SEQ ID NO: 9);(6) HCDR1: SYPMS (SEQ ID NO: 7), HCDR2: TISTGGTYTYYPDSVKG (SEQ ID NO: 8), HCDR3: QGPILRKNYYYGMDV (SEQ ID NO: 11);(7) HCDR1: SYPMS (SEQ ID NO: 7), HCDR2: TISTGGTYTYYPDSVKG (SEQ ID NO: 8), HCDR3: QGPIYYGNYYYGMDV (SEQ ID NO: 12);(8) HCDR1: SYAMS (SEQ ID NO: 1), HCDR2: TISTGGSHTYYPDSVKG (SEQ ID NO: 13), HCDR3: HGYLLYDGYYEWYFDV (SEQ ID NO: 14);(9) HCDR1: SYAMS (SEQ ID NO: 1), HCDR2: TISTGGSHTYYPDSVKG (SEQ ID NO: 13), HCDR3: HGYLLYDGYYEWYFDY (SEQ ID NO: 140);(10) HCDR1: SYAMS (SEQ ID NO: 1), HCDR2: TISTGGSHTYYPESVKG (SEQ ID NO: 15), HCDR3: HGYLLYEGYYEWYFDY (SEQ ID NO: 16);(11) HCDR1: GYPMS (SEQ ID NO: 17), HCDR2: TISTGARHTYYPDSVKG (SEQ ID NO: 18), HCDR3: HEGLRRGKYHCIMDY (SEQ ID NO: 19);Attorney Docket No. 0487.0001-US (12) HCDR1: GYPMS (SEQ ID NO: 17), HCDR2: TISTGARHTYYPDSVKG (SEQ ID NO: 18), HCDR3: HEGLRRGKYHSIMDY (SEQ ID NO: 20); and(13) HCDR1, HCDR2, HCDR3 as shown in (1)-(12), but at least one of which includes one, two, three, four or five amino acids addition, deletion, conservative amino acid substitution or the combinations thereof; and LCDR1, LCDR2, and LCDR3 are selected from a group consisting of:(1) LCDR1: TGNSNNVGDQGAV (SEQ ID NO: 21), LCDR2: RNNNRPS (SEQ ID NO: 22), LCDR3: STWDSGLNSVV (SEQ ID NO: 23);(2) LCDR1: TGNSNNVGDQGAV (SEQ ID NO: 21), LCDR2: RNNNRPS (SEQ ID NO: 22), LCDR3: STWDKNNKSVV (SEQ ID NO: 24);(3) LCDR1: SGSSSNIGSNTVN (SEQ ID NO: 25), LCDR2: SNNQRPS (SEQ ID NO: 26), LCDR3: EVWDDSLNGPV (SEQ ID NO: 27); (4) LCDR1: RSSQSLVHSDGNTYLH (SEQ ID NO: 28), LCDR2: KVSNRFS (SEQ ID NO: 29), LCDR3: SQSTHVPYT (SEQ ID NO: 30);(5) LCDR1: RSSQSLVDGEDGTYLN (SEQ ID NO: 31), LCDR2: KVSERFD (SEQ ID NO: 32), LCDR3: SQSTHVPYT (SEQ ID NO: 30);(6) LCDR1: RSSQSLVDGQDGTYLH (SEQ ID NO: 33), LCDR2: KVSNRFD (SEQ ID NO: 34), LCDR3: SQSTHVPYT (SEQ ID NO: 30);(7) LCDR1: RSSQSLVNQEGETYLH (SEQ ID NO: 35), LCDR2: KVSNRFD (SEQ ID NO: 34), LCDR3: SQSTHVPYT (SEQ ID NO: 30);(8) LCDR1: KASQSVDYDGHSFLN (SEQ ID NO: 36), LCDR2: AASNLES (SEQ ID NO: 37), LCDR3: QQSTEDPPYT (SEQ ID NO: 38);(9) LCDR1: RASESVDYDGHSFIN (SEQ ID NO: 39), LCDR2: AASNKDT (SEQ ID NO: 40), LCDR3: QQSTEDPPYT (SEQ ID NO: 38);(10) LCDR1: RASQSVDYDGHSFLN (SEQ ID NO: 41), LCDR2: AASNLQS (SEQ ID NO: 42), LCDR3: QQSTEDPPYT (SEQ ID NO: 38);(11) LCDR1: KSSQSVDYDGHSFLN (SEQ ID NO: 43), LCDR2: AASNRES (SEQ ID NO: 44), LCDR3: QQSTEDPPYT (SEQ ID NO: 38);(12) LCDR1: RASESVDYDGHSFIN (SEQ ID NO: 39), LCDR2: AASNKDT (SEQ ID NO: 40), LCDR3: QQSTEDPPYT (SEQ ID NO: 38);Attorney Docket No. 0487.0001-US (13) LCDR1: RASQSVDYEGHSFLN (SEQ ID NO: 45), LCDR2: AASNLQS (SEQ ID NO: 42), LCDR3: QQSTENPPYT (SEQ ID NO: 46);(14) LCDR1: KSSQSVDYEGHSFLN (SEQ ID NO: 47), LCDR2: AASNRES (SEQ ID NO: 44), LCDR3: QQSTENPPYT (SEQ ID NO: 46);(15) LCDR1: KASQSIDYDGDSFLN (SEQ ID NO: 48), LCDR2: AASNLES (SEQ ID NO: 37), LCDR3: HQCNEDPYM (SEQ ID NO: 49);(16) LCDR1: RASESVDYDGDSFIN (SEQ ID NO: 50), LCDR2: AASNKDT (SEQ ID NO: 40), LCDR3: HQSNEDPYM (SEQ ID NO: 51);(17) LCDR1: RASESVDYDGDSFIN (SEQ ID NO: 50), LCDR2: AASNKDT (SEQ ID NO: 40), LCDR3: HQSNEDPYL (SEQ ID NO: 52);(18) LCDR1: RASESVDYDGDSFIN (SEQ ID NO: 50), LCDR2: AASNKDT (SEQ ID NO: 40), LCDR3: HQSNEDPYV (SEQ ID NO: 53);(19) LCDR1: RASQSIDYDGDSFLN (SEQ ID NO: 54), LCDR2: AASNLQS (SEQ ID NO: 42), LCDR3: QQSNEDPYV (SEQ ID NO: 55);(20) LCDR1: KSSQSIDYDGDSFLN (SEQ ID NO: 56), LCDR2: AASNRES (SEQ ID NO: 44), LCDR3: QQSNEDPYV (SEQ ID NO: 55); and(21) LCDR1, LCDR2, LCDR3 as shown in (1)-(20), but at least one of which includes one, two, three, four or five amino acids addition, deletion, conservative amino acid substitution or the combinations thereof (see claims 7 and 8).
The ’572 application is drawn to the bi-functional fusion protein of claim 1, wherein the anti- AREG antibody or the fragment thereof comprises a heavy chain variable region, and a light chain variable region, wherein the heavy chain variable region has an amino acid sequence selected from a group consisting of SEQ ID NOs: 57-69, and an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 57-69, and retaining epitope-binding activity, wherein the light chain variable region has an amino acid sequence selected from a group consisting of SEQ ID NOs: 70-89, and an amino acid sequence having at least 95% sequence identity to any one of SEQ ID NOs: 70-89, and retaining epitope-binding activity (see claims 9 and 10).
The sequences recited in the ‘572 application share 100% identity with the sequences of the present application with the same SEQ ID NO.
The ‘572 application is drawn to a pharmaceutical composition, comprising the bi-functional fusion protein of claim 1 and a pharmaceutically acceptable carrier (see claim 33).
Lastly, the ‘572 application is drawn to a method for preventing, treating and/or diagnosing fibrotic diseases, cancers and diseases associated with chronic inflammation in a subject, which comprises administering to a subject a therapeutically effective amount of the bi-functional fusion protein of claim 1, or of the pharmaceutical composition of claim 33, preferably, the fibrotic diseases include renal fibrosis, hepatic fibrosis, pulmonary fibrosis, in particular, idiopathic pulmonary fibrosis (IPF) (see claims 35 and 36).
The difference between the instant claims and the ‘572 application is that the ‘572 application is drawn to methods of using the claimed anti-AREG proteins. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
As such, the ‘572 application anticipates the present invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
17/614,673
Claims 1-13 and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 23, 25-27, and 29-36 of copending Application No. 17/614,673 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The ‘673 application is drawn to a method for treating idiopathic pulmonary fibrosis (IPF), comprising: a) administering a substance inhibiting Amphiregulin (AREG); and b) inhibiting AREG in AT2 cells of lung from an animal or a human being; wherein IPF is characterized in that the expression level of AREG is up-regulated in AT2 cells of lung from an animal or a human being suffering from progressive fibrosis (see claim 1).
The ’673 application is drawn to the method of claim 1, wherein inhibiting AREG in AT2 cells comprises inhibiting expression level of AREG in AT2 cells of lung from an animal or a human being (see claim 10).
The ‘673 application is drawn to a method for screening a drug for treating pulmonary fibrosis of an animal or a human being by using substances inhibiting AREG in AT2 cells of lung from an animal or a human being (see claims 22 and 32).
The ‘673 application is drawn to a method for diagnosing pulmonary fibrosis of an animal or a human being, comprising contacting a substance inhibiting AREG with a sample from an animal or a human being suspected suffering from pulmonary fibrosis (see claims 23 and 33).
The ‘673 application is drawn to a method for treating pulmonary fibrosis of an animal or a human being, comprising administering a subject with a therapeutically effective amount of a substance inhibiting AREG in AT2 cells (see claims 27 and 36).
The ‘673 application indicates that the animal is mouse, rabbit, rat, canine, pig, horse, cow, sheep, monkey or chimpanzee (see claims 29-31).
The difference between the present application and the ‘673 application is that the ‘673 application is drawn to a method of using a substance inhibiting AREG. However, the Federal Circuit has held that obviousness-type double patenting exists for method claims that simply claim the disclosed use of a composition in the specification. See Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F.3d 1381, 1389 (2010). The instant application and the copending application are not divisional applications resulting from restriction, and therefore no protection under the provisions of 35 USC 121.
As such, the ‘673 application anticipates the present invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Ding et al (J Immunol. 2016 July 1; 197(1): 303–312) teach that AREG is implicated in tissue repair and fibrosis (see Abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANAYA L MIDDLETON whose telephone number is (571)270-5479. The examiner can normally be reached M-F 9:30AM - 6PM with flex.
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/DANAYA L MIDDLETON/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674