DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election
Applicant’s species election without traverse in the reply filed on 05/11/2026 is acknowledged. Applicant elects: (i) an antibody or antigen-binding fragment thereof that binds CD40 as the species of antibody or antigen-binding fragment; (ii) an epitope comprising five or more of amino acids 124-132 of SEQ ID NO: 4 and/or five or more of amino acids 143-152 of SEQ ID NO: 4, or an epitope with at least 80% or greater sequence identity thereto as the species of epitope; and (iii) a cell proliferation disorder as the species of disorder or disease treated by administering the elected species of antibody or antigen-binding fragment thereof.
Status of Claims
Claims 277-299 are pending.
Claims 295-299 are new.
Claims 289-291 are withdrawn from further consideration by the Examiner under 37
CFR 1.142(b) as being drawn to a non-elected invention.
Claims 277-288 and 292-299 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 01/21/2021 based on the provisional application 63/140,081 (filed 01/21/2021).
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
b) In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – A heavy chain variable domain amino acid sequence and a light chain variable domain amino acid sequence appear on Pg 181 lines 1-6 of the specification and these have not been identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the sequence identifier, 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.
Claim objections
Claims 280, 284, 285, 286, 287, 288, 292 and 299 are objected to because of the following informalities:
Claim 280 appears to have typographical errors. The term “TNFR2” with three occurrences in the claim seems to be an error that should be amended to “TNFRSF”. For example, “TNFR2 antibodies” should be “TNFRSF antibodies, while “that bind TNFR2” should be “that bind TNFRSF”.
Claim 284 appears to have a typographical error. The punctuation of “.” in the sentence “(a) the host cell is a prokaryotic cell.” should be amended to “;”.
Claim 284 is objected to because the claim is lacking a conjunction between the recited limitations of (a) and (b) in the claim. It is suggested that the word “or” be inserted after the phrase “(a) the host cell is a prokaryotic cell;” in claim 284. Claim 297 is objected to because of similar issues in the claim. Claim 296 is lacking a conjunction between the recited limitations of (i) and (ii). It is suggested that the word “or” be inserted after the phrase “(i) has an IgG isotype, optionally wherein the IgG isotype is an IgG2 isotype;”.
Claims 285 and 292 appear to have several typographical errors. For claim 285, firstly, the abbreviation of “(CAR-T)” in line 7 of Pg 8 does not correspond to the preceding term of “chimeric antigen receptor”. The abbreviation should be amended to “(CAR)”. Secondly, the phrase “an anti-Ceacan 1 agent” is likely to mean “an anti-CEACAM1 agent” in line 13 of Pg 8 of the claim set. Thirdly, it is noted that in line 15 of Pg 8, the phrase “an anti-CEACAM1 agent” has already been recited which means this phrase may need to be deleted. Fourthly, the sentence is missing a comma punctuation in line 16 between “an anti-CR5 agent” and “an anti-CD95 agent” where the phrase should be amended to read “…..an anti-CR5 agent, an anti-CD95 agent…..”. Claim 292 also has the same issues as those outlined for claim 285.
Claim 286 appears to have several typographical errors. In “(c)”, the sentence is missing the phrase “of claim 277” which is suggested to be added, such that the sentence should read “(c) a polynucleotide encoding the antibody or antigen-binding fragment thereof of claim 277;”. A similar amendment is suggested for “(f)” such that the sentence should read “(f) a pharmaceutical composition comprising the antibody of antigen-binding fragment thereof of claim 277.”.
Claim 287 appears to have several typographical errors. In line 2 of the claim on Pg 8, the word “or” before “osteoporosis” seems to be unnecessary. In “(c)”, the sentence is missing the phrase “thereof of claim 277” which is suggested to be added, such that the sentence should read “(c) a polynucleotide encoding the antibody or antigen-binding fragment thereof of claim 277;”. A similar amendment is suggested for “(f)” such that the sentence should read “(f) a pharmaceutical composition comprising the antibody of antigen-binding fragment thereof of claim 277.”.
Claim 288 appears to have several typographical errors. The following diseases should have the first word written in capital letter: (1) “wilms tumor” should be “Wilms tumor”; (2) “merkel cell carcinoma” should be “Merkel cell carcinoma”; and (3) “sézary syndrome” should be “Sézary syndrome”.
Claim 299 appears to have a typographical errors. The option of “(f)” in line 7 should be amended to “(c)”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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 280, 281, 284, 286, 287 and 295-299 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 280 is rejected because it is unclear how the peptides of SEQ ID NOs: 67, 68 and 69 are related to the TNFRSF member proteins recited in claim 277. It is noted that these peptide sequences are comprised within the extracellular domain of human TNFR2 protein (as taught by Faustman in WO2017040312A1 Date Published 2017-03-09). However, TNFR2 is not one of the TNFRSF member protein recited in claim 277 which claim 280 depends from.
Claim 281 is rejected because the claim recites the word “preferably”. The metes-and-bounds of the claim is unclear because it is unclear how, or if, possible limitations following “preferably” limit the claim. Description of preferences should be properly set forth in the specification rather than the claims. If stated in the claims, preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made. The Examiner should analyze whether the metes and bounds of the claim are clearly set forth. Examples of claim language which have been held to be indefinite are (A) "a temperature of between 45 and 78 degrees Celsius, preferably between 50 and 60 degrees Celsius"; and (B) "a predetermined quantity, for example, the maximum capacity."
Claim limitation “means for binding an epitope within CD40” in claim 295 and dependent claims 296-299 invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. There is insufficient disclosure of the corresponding structure of the antibody or antigen-binding fragment thereof for performing the entire claimed function and there is no clear linkage between the structure and the function of binding to the recited epitopes on CD40 because the specification is devoid of any structure that performs the function in the claim and there is no association between the structure of the antibody or antigen-binding fragment thereof and the function of specifically binding to recited CD40 epitopes can be found in the specification. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 277-288 and 292-299 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the Claimed Genus
In the instant case, Instant claims 277-288 and 292-299 are inclusive of (i) a genus of an antibody or antigen binding fragment thereof that specifically binds a human tumor necrosis factor receptor superfamily (TNFRSF) member protein, wherein the antibody or antigen-binding fragment thereof specifically binds CD40, wherein the antibody or antigen-binding fragment thereof specifically binds an epitope comprising five or more of amino acids 124-132 of SEQ ID NO: 4 and/or five or more of amino acids 143-152 of SEQ ID NO: 4, or an epitope with at least 80% or greater sequence identity thereto (elected species) and (ii) a genus of antibodies and antigen-binding fragments thereof that bind each recited epitope or variant thereof. In short, the genus includes antibodies or antigen binding fragments thereof that have the required function of specifically binding to specific peptide epitopes on each of the TNFRSF member proteins recited in the claims which includes the elected species of “five or more amino acid sequence” epitopes on CD40 (instant SEQ ID NO: 4). Accordingly, the claims encompassing countless possible antibodies or antigen-binding fragments thereof that specifically bind the recited TNFRSF member proteins which are described only by the target to which they bind. The antibody function has been recited but without a correlation to which structure(s) can perform said recognition to recited epitopes on recited TNFRSF member proteins.
Summary of Species Disclosed in the Specification
The instant specification discloses in Figure 1A to V the epitopes within each of the twenty-two recited TNFRSF member proteins. With respect to the elected species, the instant specification discloses in Figure 1A the amino acid sequence of human CD40 (SEQ ID NO: 4) wherein underlined amino acids SCSPGFGVK (SEQ ID NO: 25) which correspond to residues 124-132 of SEQ ID NO: 4 and amino acids CEPCPVGFFS (SEQ ID NO: 26) which correspond to residues 143- 152 of SEQ ID NO: 4 are define epitopes, such that one or more amino acids of one or both of SEQ ID NOs: 25 and 26 may be bound by a CD40 antagonist (e.g., an antagonistic polypeptide, such as a single-chain polypeptide, antibody, or antigen-binding fragment thereof) (Pg 46-47). The specification also discloses that even though these amino acid residues are not consecutive in primary sequence, they are likely spatially proximal in the three dimensional tertiary structure of CD40 and may be appropriately positioned for interaction with an antagonistic CD40 antibody of the disclosure (Pg 47). The specification further discloses that some or all of the amino acids of the epitope(s), or one or more amino acids in a region next to the epitope(s), or spatially near or next to the epitopes based on the tertiary structure of CD40, may be bound by a CD40 antagonist to achieve antagonism of CD40 (Pg 47). However, no specific CD40 binding antibody or antigen-binding fragment thereof with structural amino acid sequence was disclosed for said antibody. Likewise, for the rest of the recited TNFRSF member proteins, no specific structural information on the amino acid sequence of the binding antibodies or antigen-binding fragments were disclosed in the specification.
In addition, instant specification on Pg 95-96 discloses that TNFRSF member antagonists of the disclosure may be in the form of a single-chain polypeptide, such as a single-chain polypeptide that contains one, two, or three heavy chain CDRs of a monoclonal TNFRSF member antagonist antibody described herein, and/or one, two, or three light chain CDRs of a monoclonal TNFRSF member antagonist antibody described. The specification also discloses that single-chain polypeptides may be in the form of an antibody fragment, e.g., an antibody fragment described herein or known in the art, such as a scFv fragment. However, no specific CDR amino acid sequences of any TNFRSF member binding antibody or antigen-binding fragment thereof were disclosed.
Further instant specification on Pg 104-105 discloses that libraries of cyclic and polycyclic peptides comprising the sequence of any one of SEQ ID NOs: 25-66 which correspond to individual fragments isolated from TNFRSF members and combinations of fragments from distinct regions of TNFRSF members can be synthesized and used to screen libraries of antibodies and antigen-binding fragments thereof in order to identify anti-TNFRSF member polypeptides. The specification also discloses that since these constrained peptides act as surrogates for epitopes within TNFRSF members that promote receptor antagonism, polypeptides (e.g., single-chain polypeptides, antibodies, and antigen-binding fragments thereof) generated using this screening technique may bind the corresponding epitopes in TNFRSF members and are expected to be antagonistic of receptor activity. However, no specific structure for the TNFRSF member binding antibodies or antigen-binding fragments thereof were disclosed following the disclosure of the method used for screening antibodies that specifically recognized distinct epitopes and which had distinct functions when bound to said epitopes on the TNFRSF members.
In conclusion therefore, the written description does NOT convey the structural information of any species of the elected antibody that specifically binds the epitope(s) on CD40 as is recited in the instant claims, nor does it convey the same for any antibody that could specifically bind to any of the other recited epitopes on any of the other TNFRSF member proteins recited in the claims.
State of the Prior Art and Structure/Function Correlation
As is well-known in the antibody art at the time of filing, the formation of an intact antigen-binding site in an antibody typically requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope (reviewed in Sela-Culang et al. Frontiers in immunology 4 (2013): 302. 1-13).
Sela-Culang further teaches that antigens lack intrinsic properties that clearly differentiate between epitopic and non-epitopic residues, and any part of the antigen surface may become part of an epitope under some circumstances (“Ab Epitope Prediction”; Pg. 2). In the same context, Edwards et al. (Journal of molecular biology 334.1 (2003): 103-118) endeavored to uncover the breadth of the structural diversity of antibodies a single antigen can give rise to. Edwards et al. employed a phage display library to screen for antibodies that bind a single protein, BLyS, and isolated over 1000 unique anti-BLyS antibodies, each comprising a different amino acid sequence (Abstract). These antibodies were structurally diverse, resulted from nearly all possible Vh, D, and Jh, germlines (Pg. 105; “Vh and Vl germline usage”), and comprised 568 distinct Vh CDR3 sequences, ranging in length from 5 to 25 amino acid residues (Fig. 4; “Vh CDR3 sequence diversity”; Pg. 105). Together, these works highlight that neither knowledge of the antigen sequence nor the antibody sequence is necessarily predictive of its function.
With regards to the elected species, Takahashi et al. (US20070148163A1 Date Published 2007-06-28) teaches a method of determining the epitopes of antibodies that recognize CD40 wherein eighty-two 13-mer peptides covering the extracellular region of CD40 were synthesized and tested for antibody recognition (paragraph [0261]). They teach that antibody F76 strongly recognizes SEQ ID NO: 99 (LHRSCSPGFGVKQ) and SEQ ID NO: 100 (RSCSPGFGVKQIA) (paragraph [0262] and see Pg 26-27 of the instant Office Action 102 rejection below). It is noted that the bold amino acid sequence in SEQ ID NOs: 99 and 100 of Takahashi et al. which is “SCSPGFGVK”, is an exact match to amino acids 124-132 of instant SEQ ID NO:4 (which is the full sequence of human CD40). The teachings in the prior art of this single antibody that recognizes amino acids 124-132 of instant SEQ ID NO:4 however does not adequately describe the claimed genus. One of skill in the art would recognize that a known antibody that binds an epitope does not adequately describe any other antibody that binds the same epitope and certainly does not describe the claimed genus of antibodies that bind amino acids 124-132 of instant SEQ ID NO:4.
In addition, because the claims encompass countless possible antibodies or antigen-binding fragments thereof that can specifically bind one of the twenty-two recited TNFRSF member proteins by only describing the target epitopes to which they bind, the prior art thus does not adequately describe the claimed antibodies or fragments thereof.
Further, in view of Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017) and the Office’s February 2018 memo clarifying written description guidance for claims drawn to antibodies, the 2008 Written Description Training Materials are outdated and should not be relied upon as reflecting the current state of law regarding 35 U.S.C. 112. Further, a “newly characterized antigen” test flouts basic legal principles of the written description requirement (Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017)). Adequate written description of a newly characterized antigen alone is not considered adequate written description of a claimed antibody to that newly characterized antigen. Where an antibody binds to an antigen tells one nothing about the structure of any other antibody. Also, see the Board’s decision in Appeal 2017-010877 (claims to “A monoclonal antibody that binds a conformational epitope formed by amino acids 42-66 of SEQ ID NO:1”).
The functional requirements of the claimed antibodies is the sort of wish list of properties which fails to satisfy the written description requirement because “antibodies with those properties have not been adequately described.” Centocor, 636 F.3d at 1352.
The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.”Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Accordingly, the skilled artisan would be unable to envisage the structure of an antibody that binds any one of the recited TNFRSF member proteins or any particular epitopes thereof a priori given the current state of the antibody arts.
Guidance on When Disclosed Species are Representative of the Claimed Genus
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common to that genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The inventions at issue in Lilly were DNA constructs per se, the holdings of that case is also applicable to claims such as those at issue here.
Further, disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product. See Ariad, 598 F.3d at 1354-55 (“Regardless whether the asserted claims recite a compound, Ariad still must describe some way of performing the claimed methods... the specification must demonstrate that Ariad possessed the claimed methods by sufficiently disclosing molecules capable of reducing NF-kB activity so as to ‘satisfy the inventor' s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed.' ”) (internal citation omitted); see also Univ. of Rochester v. G.D. Searle& Co., Inc., 358 F.3d916,918 (Fed.Cir.2004) (applying the same analysis to assess written description for claims to a “method for selectively inhibiting” a particular enzyme by administering a functionally defined compound, i.e., a “non-steroidal compound that selectively inhibits activity” of the gene product for that enzyme).
In regards to claims to a product defined by function, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 at1568 USPQ2d at 1406 (“definition by function…does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”). Further, the functional requirements of the claimed antibodies are the sort of wish list of properties which fails to satisfy the written description requirement because “antibodies with those properties have not been adequately described.” Centocor, 636 F.3d at 1352. The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim' s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.”Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Further, Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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). Even though Applicant may propose methods of screening for possible members of the genus, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore conception is not achieved until reduction to practice has occurred, 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 of isolation. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. See Ariad, 94 USPQ2d at 1161; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. 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).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification that discloses no species provides neither a representative number of species antibodies or antigen-binding fragment thereof that encompass the genus of antibodies or antigen-binding fragments thereof that is capable of specifically binding an epitope comprising amino acid sequences on any of the TNFRSF member proteins as recited in the claims; nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
Conclusion
Since the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus is highly variant, the disclosure of no species of antibodies or antigen-binding fragments thereof that is capable of specifically binding, for the elected species: an epitope comprising five or more of amino acids 124-132 of SEQ ID NO: 4 and/or five or more of amino acids 143-152 of SEQ ID NO: 4, or an epitope with at least 80% or greater sequence identity thereto wherein SEQ ID NO: 4 is the full amino acid sequence of CD40; or for any of the other TNFRSF member proteins: an epitope comprising amino acid sequences on the TNFRSF member proteins as recited in the claims, that can be found in the specification is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed. Written description can be met if the claims recite the minimal structure that is needed to perform the function recited in the claims without any variability.
Claim Rejections - 35 USC § 112(f)
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
In particular, claim 295 and dependent claims 296-299, recite an antibody or antigen-binding fragment thereof that specifically binds CD40 comprising a means for binding an epitope within CD40 comprising five or more of amino acids 124-132 of SEQ ID NO: 4 and/or five or more of amino acids 143-152 of SEQ ID NO: 4, or an epitope with at least 80% or greater sequence identity thereto. The term “means for binding” is not modified by sufficient structure or materials for performing the claimed function in claim 295, and is thus being interpreted under U.S.C. 112(f). Claims 296-299 which depend from or recite the antibody or antigen-binding fragment thereof of claim 295 and also do not disclose sufficient structure or materials for performing the claimed function, are similarly interpreted under U.S.C. 112(f).
With respect to the structure of the “means for binding” that corresponds to the instantly claimed functional properties of the antibody or antigen-binding fragment thereof, the specification has not disclosed any structural details of any antibody or antigen-binding fragment thereof that can bind CD40. Because this limitation is being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, the interpretation to cover any structural elements described in the specification that can sufficiently modify the “means for binding” of the antibody or antigen-binding fragment thereof is lacking.
Claim Rejections - 35 USC § 112
Claim Rejections - Improper Markush Grouping
Claims 277-288 and 292-294 are rejected on the basis claims 277 and 280 contain improper Markush groupings of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of instant claims 277 and 280 are improper because the alternatives defined by the Markush groupings do not share both a single structural similarity and a common use for the following reasons:
Instant claim 277 contains a Markush group of antibodies or antigen-binding fragment thereof that can bind to TNFRSF member proteins that are structurally diverse as can be appreciated in Figures 1A to 1V (SEQ ID NOs: 1-22), giving rise to antibodies that are not functionally equivalent and so are expected or predicted to not share a single structure. Therefore, no common, substantial structural feature essential to their utility is shared by every member of the group and so the Markush groups are not proper and the claims are rejected here.
In addition, instant claim 280 contains a Markush group of peptides comprising amino acid sequences of SEQ ID NOs: 25-153 that are structurally diverse. As an example, sequence alignment of instant SEQ ID NO: 25 (SCSPGFGVK) with instant SEQ ID NO: 100 (LSXGSRCSSDQGGSGGCTXRPGWYXAL) show that the two sequences only share 27.% identity (see alignment below). This is not unexpected since SEQ ID NO: 25 is a peptide sequence from CD40 while SEQ ID NO: 100 is a peptide sequence that consists of three X amino acid residues where X is Cys residue protected with ACM protecting group.
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To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 277 is rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Takahashi et al. (US20070148163A1 Date Published 2007-06-28).
Takahashi et al. teaches potentially therapeutic anti-CD40 antibodies comprising at least one mutation or substitution in the constant region and having at least a hinge region derived from a human IgG2 (Abstract). They teach a method of determining the epitopes of antibodies that recognize CD40 wherein 82 peptides (SEQ ID NOs: 49 to 130) that are 13-mers in length covering the extracellular region of CD40 were synthesized and tested for antibody recognition (paragraph [0261]). They also teach that antibody F76 strongly recognizes SEQ ID NO: 99 and 100 (they explicitly teach that F76 strongly recognizes the 51st and 52nd peptides; mathematically, it is worked out that SEQ ID NO: 99 is the 51st number in a sequence of consecutive whole numbers starting from 49 to 130, while SEQ ID NO: 100 is the 52nd number of the said sequence of consecutive whole numbers) (paragraph [0262]).
Sequence alignment of SEQ ID NOs: 99 and 100 taught by Takahashi et al. with those of amino acids 124-132 of instant SEQ ID NO: 4 shows that there is 100% match between them.
Alignment of amino acids 124-132 of instant SEQ ID NO: 4 (top) with SEQ ID NO: 99 taught by Takahashi et al. (bottom)
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Alignment of amino acids 124-132 of instant SEQ ID NO: 4 (top) with SEQ ID NO: 100 taught by Takahashi et al. (bottom)
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Therefore, Takahashi et al. teaches an antibody that specifically binds to CD40 wherein the epitope comprises amino acids 124-132 of instant SEQ IDNO: 4. Takahashi et al. also teaches that the antibody that binds CD40 at the recited epitope comprises a non-native constant region by teaching that the anti-CD40 antibodies comprise at least one mutation or substitution in the constant region.
Therefore, the antibody of Takahashi et al. anticipates instant claim 277 and is thus rejected here.
Claim Rejections - 35 USC § 103 (First)
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 277-280 and 282-285 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al. (US20070148163A1 Date Published 2007-06-28) as applied to claim 277 above, and further in view of additional teachings of Takahashi et al. (US20070148163A1 Date Published 2007-06-28).
The teachings of Takahashi et al. have been described in the 102 rejection above.
Takahashi et al. does not specifically teach the antibody or antigen-binding fragment thereof of instant claim 277, wherein the antibody or antigen-binding fragment thereof comprises a non-native constant region or has an IgG isotype; or wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof.
Takahashi et al. also does not specifically teach a method of producing the antibody or antigen-binding fragment thereof of instant claim 277, said method comprising expressing a polynucleotide encoding said antibody or antigen-binding fragment thereof in a host cell and recovering the antibody or antigen-binding fragment thereof from host cell medium.
Takahashi et al. further does not specifically teach a polynucleotide encoding the antibody or antigen-binding fragment thereof of instant claim 277; or a vector comprising the said polynucleotide; or an isolated host cell comprising said vector; or a pharmaceutical composition comprising the antibody or antigen- binding fragment thereof of instant claim 277.
However, Takahashi et al. teaches monoclonal antibodies that are capable of binding to CD40 include human IgG1, IgG2, IgG3 or IgG4 heavy chain (paragraphs [0068] and [0170]). They teach that the P331S mutation introduced into the IgG2 constant region of anti-CD40 antibodies resulted in a decrease in complement-dependent cytotoxicity (CDC) activity (paragraph [0274]). They also teach that anti-CD40 antibodies can be provided by incorporating an antibody gene into an expression vector, transfecting the vector into a suitable host cell, harvesting the antibody from the cultured cells or the supernatant, and purifying it (paragraphs [0243], [0068] and [0170]). They further teach a pharmaceutical composition comprising said anti-CD40 monoclonal antibodies (paragraphs [0068] and [0170]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making the antibody of F76 as taught by Takahashi et al. which is an antibody that binds to CD40 (a member of TNFRSF) and specifically recognizes the epitope comprising five or more of amino acids 124-132 of instant SEQ ID NO: 4, and wherein the antibody comprises a P331S mutation introduced into the IgG2 constant region resulting in a non-native constant region, also as taught by Takahashi et al., because Takahashi et al. teaches that said mutation on the IgG2 constant region of anti-CD40 antibodies decreases CDC activity for optimizing said antibodies as pharmaceutical agents (paragraph [0274] and Abstract). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
With regards to instant claim 279, wherein the antibody is a monoclonal antibody, one of ordinary skill in the art would have been motivated with a reasonable expectation of success, to perform a combined method of making the antibody of F76 as taught by Takahashi et al. as a monoclonal antibody as taught by Takahashi et al. because monoclonal antibodies have the advantages of having high specificity, consistent reproducibility and scalable production as a therapeutic.
With regards to instant claim 280, one of ordinary skill in the art would have been motivated with a reasonable expectation of success, to perform a combined method of producing the antibody of F76 as taught by Takahashi et al. wherein the method comprises expressing a polynucleotide encoding antibody F76 in a host cell and harvesting the antibody from the cultured supernatant as taught by Takahashi et al. because these are routine molecular biology techniques for antibody expression for one ordinarily skilled in the art.
With regards to instant claim 282, a polynucleotide encoding said antibody, Takahashi et al. teaches anti-CD40 antibody genes. Therefore, one of ordinary skill in the art would have been motivated with a reasonable expectation of success, to perform a combined method of making the polynucleotide encoding the antibody of F76 because this is a routine molecular biology techniques for antibody expression for one ordinarily skilled in the art. Likewise, with regards to instant claim 283, a vector comprising the polynucleotide of instant claim 282; and instant claim 284, an isolated host cell comprising the vector of instant claim 283, these are routine molecular biology techniques for antibody expression for one ordinarily skilled in the art.
With regards to instant claim 285, one of ordinary skill in the art would have been motivated with a reasonable expectation of success, to perform a combined method of making a pharmaceutical composition as taught by Takahashi et al. that comprises the antibody of F76 as taught by Takahashi et al. because a pharmaceutical composition comprising said antibody would have the advantages of enhanced stability and shelf-life as well as ease for patient administration.
Claim Rejections - 35 USC § 103 (Second)
Claim(s) 277-280, 282-285 and 294 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al. (US20070148163A1 Date Published 2007-06-28) as applied to claims 277-280 and 282-285 above, and further in view of Sarawar et al. (WO0066155A1 also known as WO2000066155A1 Date Published 2000-11-09).
The teachings of Takahashi et al. have been described in the 102 rejection and first 103 rejection above.
Takahashi et al. does not specifically teach a kit comprising the pharmaceutical composition of instant claim 285 and instructions for administering the pharmaceutical composition to a human.
However, these deficiencies are made up in the teachings of Sarawar et al.
Sarawar et al. teaches a method for modulating CD4 T cell function by administration of antibodies that specifically bind to cell surface expressed CD40 to an individual that can be a human (Abstract and claims 1 and 8). They teach a kit comprising a pharmaceutical composition comprising an antibody that specifically binds to a cell-expressed CD40, and printed matter comprising instructions for using the pharmaceutical composition, wherein the instructions indicate use of the pharmaceutical composition to prevent latent virus reactivation or to control virus replication (Pg 4 lines 10-18).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a kit that comprises a pharmaceutical composition comprising an antibody that specifically binds to a cell-expressed CD40, as well as comprises a printed matter comprising instructions for using the pharmaceutical composition in humans as taught by Sarawar et al. and substituting the CD40 antibody of Sarawar et al. with the antibody that specifically binds to the epitopes on CD40 as taught by Takahashi et al. This is because a kit provides the advantages of improved ease of administration of the antibody that is stable and at a precise dose in a pharmaceutical composition that is formulated for human administration. In addition, the provision of clear instructions in the kit further supports adherence, reduces adverse events and ensures usage guidelines are available at point of care. This is an example of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (Third)
Claims 277--285 and 295-298 are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi et al. (US20070148163A1 Date Published 2007-06-28) as applied to claims 277-280 and 282-285 above, and further in view of Sela-Culang et al. (Front. Immunol. 4 (2013):302, 1-13).
The teachings of Takahashi et al. have been described in the 102 rejection and the first 103 rejection above.
Takahashi et al. does not specifically teach a construct comprising a first polypeptide domain and a second polypeptide domain, wherein the first polypeptide domain and the second polypeptide domain are each, independently, an antigen-binding fragment of instant claim 277.
Takahashi et al. also does not specifically teach an antibody or antigen-binding fragment thereof that specifically binds CD40 comprising: (a) means for binding an epitope within CD40 comprising five or more of amino acids 124-132 of instant SEQ ID NO: 4; and (b) an Fc region.
However, these deficiencies are made up in the teachings of Sela-Culang et al.
Sela-Culang et al. teaches the full antibody structure comprises two Fab regions that are responsible for creating the antigen binding site or paratope, and constant heavy chains CH2 and CH3 that compose the Fc region that is responsible for mediating the biological activities of the antibody molecule (Figure 2A and 2B and Pg 3 column left, first full paragraph). They teach that antibody constant domains are responsible for the isotype and for effector function, such as complement activation, Fc receptor binding, avidity, serum half-life as well as a role in antigen binding affinity (Pg 8 column left, first full paragraph, lines 1-10).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making a construct comprising a first polypeptide domain and a second polypeptide domain, wherein the first polypeptide domain and the second polypeptide domain are each, independently, an antigen-binding fragment as taught by Sela-Culang et al. as two Fab regions that are comprised within a full antibody molecule and replacing the antigen-binding fragments as taught by Sela-Culang et al. with the antigen binding fragment that specifically binds an epitope on CD40 comprising five or more of amino acids 124-132 of instant SEQ ID NO: 4, which is antibody F76 as taught by Takahashi et al. because these are routine molecular biology techniques for antibody engineering for one ordinarily skilled in the art to make antibodies that have different targets and still maintain the full IgG antibody structure. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
In addition, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making an antibody that specifically binds CD40 comprising a means for binding an epitope within CD40 comprising five or more of amino acids 124-132 of instant SEQ ID NO: 4 which is antibody F76 as taught by Takahashi et al. and combining said antibody with the Fc region as taught by Sela-Culang et al. because Sela-Culang et al. teaches that the antibody Fc region is responsible for mediating biological activities of the antibody molecule, as such the antibody made from the combined method which comprises a Fc region would have the advantage of being capable of actively mediating biological activities that are desired for superior therapeutic effects. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
No claims are allowed.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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