DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-12 are pending and are under examination.
The nonstatutory double patenting rejections over the ‘769 patent and ‘987 patent are withdrawn in view of Applicant’s terminal disclaimer filed 11/6/25.
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.
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 1-12 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.
Claim limitation “means for” 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.
The present claims are directed to an anti-LAG-3 antibody comprising “means for” binding to domain 3 of human LAG-3, while allowing human LAG-3 to bind to MHC-II and allowing human LAG-3 to exert human T cell suppression function. The instant specification discloses rat anti-human LAG-3 VH and VL sequences that bind to domain 3 of human LAG-3 having SEQ ID NO: 2/4, or 6/8, or 10/12, or 14/16 or 18/20 (or having CDR sequences therefrom in SEQ ID NO: 40-46, SEQ ID NO: 47-52, SEQ ID NO: 53-58, SEQ ID NO: 59-64, or SEQ ID NO: 65-70, or humanized VH and VL thereof in SEQ ID NO: 28 or 30 and SEQ IQ NO 32, 34, 36, 38, or 49). However, the specification does not clearly link the genus of structures above to the claimed function of binding to LAG-3 while allowing human LAG-3 to bind to MHC-II and allowing human LAG-3 to exert human T cell suppression function. For example, on pages 5-6, the specification discloses particular antibody VH/VL or CDR sequences, that function according to a list of different functions that include the claimed functions, wherein the functions are listed in the alternative, i.e. allowing bind to MHC-II or allowing T suppression function. The specification does not clearly disclose which structures of the genus of different antibody structures correlate with both claimed functions. For example, in the examples, the only structure specifically tested for the function of allowing human LAG-3 to exert human T cell suppression was an antibody having VH/VL of humanized hLA212_H3/L2 (i.e. VH of SEQ ID NO: 30 and VL of SEQ ID NO: 34).
Furthermore, the specification also discloses that the invention encompasses antibody mutants, meaning those having 1-50 amino acid substitution, additions, or deletions (see paragraph 125, in particular). The specification also discloses that the invention encompasses bird derived or human VH/VL, VH and VL domains comprising CDRs exchanged there among, CDR mutants of the above VH/VL sequences, VH and VL at least 80% identical to the above VH/VL, and VH/VL encoded by any nucleic acid sequence that hybridizes to a nucleic acid sequence encoding the above VH/VL (see pages 11-12, paragraph 135, 161-165, 187-193, and 236-241, in particular). The human VH/VL, for example, are described in broad generic terms that does not allow one skilled in the art to identify the corresponding structure for performing the recited function.
Whether a claim reciting an element in means- (or step-) plus-function language fails to comply with 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, because the specification does not disclose adequate structure (or material or acts) for performing the recited function is closely related to the question of whether the specification meets the description requirement in 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. A means- (or step-) plus- function claim limitation that invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, is appropriate if one of ordinary skill in the art cannot identify what structure, material, or acts disclosed in the written description of the specification perform the claimed function. See MPEP 2181-2187. For example, while the specification generically discloses bird or human antibody VH/VL structures can be used, no specific structure representing a bird or human binding means are disclosed. Furthermore, inadequate disclosure is provided to establish what structures (CDR residues, VH/VL sequences, those 80% identical, or which mutants, or hybridizing nucleic acids) would be capable of performing the entire claimed function.
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.
Applicant’s arguments filed 11/6/25 have been fully considered, but they are not persuasive.
Applicant argues that as recognized in Ex parte Chamberlain (ARP 2024), the specification satisfies the 112a and 112b requirements so long as it describes one antibody structure that performs the claim function. Applicant argues that the specification explicitly disclose the structure of at least one antibody, i.e. the hLA212 antibody of SEQ ID NO: 30 and 34. Applicant argues that the bird-derived antibodies, percent identity variants, and human antibodies would represent permissible equivalents of the disclosed antibody structure, and the speciation is not required to describe equivalents to meet the definiteness or written description requirement.
The issue is not that the specification fails to describe “equivalents” of the disclosed structure, but rather that the specification fails to clearly describe what structure, material, or acts perform the claimed function. In Ex parte Chamberlain only a single antibody structure was disclosed, the 5G1.1 antibody. However, the instant application discloses numerous structural genuses of different antibodies that are explicitly disclosed as meeting the claimed function. For example, in paragraph 236, the specification discloses that antibodies having the properties of (3-2) to (3-8) (which correspond to the claimed functions) are antibodies comprising a heavy chain and a light chain having 80% amino acid sequence identity to rLA204, rLA212, rLA225, rLA869, RLA1264, cLA204, cLA211, hLA212, etc. See pages 28, 31-32 of the specification wherein property (3-2) is disclosed as the function of binding to domain 2 of LAG-3, property (3-7) is the function of allowing human LAG-3 to bind to human MHC class II molecules, and property (3-8) is the function of allowing human LAG-3 to exert human T cell suppression (See pages 28, 31-32). In other words, the specification contemplates the structure corresponding to the claimed functions are those having 80% sequence identity to, for example hLA212 (i.e. SEQ ID NO: 30/34). This defines a genus of structures; however, the specification does not adequately define which specific sequences among the genus of sequences correspond to the claimed function. Likewise, the specification on page 50 discloses that antibodies with the claimed function (3-2) to (3-8) encompass human antibodies, and on page 60 discloses that the human antibodies are found in a human antibody phage library. The phage library comprising human antibodies represents a structure, however, the specification does not adequately define which antibody sequences amount the various human antibody structures found therein would correspond to the claimed function.
See MPEP 2181. To satisfy the definiteness requirement under 35 U.S.C. 112(b) or 35 U.S.C. 112, second paragraph, the written description must clearly link or associate the corresponding structure, material, or acts to the claimed function. Telcordia Techs., Inc. v. Cisco Systems, Inc., 612 F.3d 1365, 1376, 95 USPQ2d 1673, 1682 (Fed. Cir. 2010). The requirement that a particular structure be clearly linked with the claimed function in order to qualify as corresponding structure is the quid pro quo for the convenience of employing 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, and is also supported by the requirement of 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, that an invention must be particularly pointed out and distinctly claimed. Thus, the means- (or step-) plus- function claim must be analyzed to determine whether there exists corresponding adequate support for such claim limitation under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. In considering whether there is 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph support for the claim limitation, the examiner must consider whether the specification describes the claimed invention in sufficient detail to establish that the inventor or joint inventor(s) had possession of the claimed invention as of the application's filing date.
The Federal Circuit has recognized the problem of providing a sufficient disclosure for functional claiming, particularly with generic claim language, explaining that “The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result. But the specification must demonstrate that the applicant [inventor] has made a generic invention that achieves the claimed result and do so by showing that the applicant [inventor] has invented species sufficient to support a claim to the functionally-defined genus.” Ariad Pharmaceuticals Inc. v. Eli & Lilly Co., 598 F.3d 1336, 1349, 94 USPQ2d 1161, 1171 (Fed. Cir. 2010) (en banc).
Applicant argues that any other embodiments disclosed by the instant specification as meeting the claimed function, other than the hLA212 antibody of SEQ ID NO: 30 and 34, such as the disclosed human antibodies, 80% identical antibodies, avian antibodies would be equivalents, and therefor encompassed by the instant claims. However, Applicant’s claim construction as these being “equivalents” would allow the claim to cover the very subject matter that is not adequately defined, described or enabled. See MPEP 2181, the invocation of 35 U.S.C. 112(f) does not exempt an applicant from compliance with 35 U.S.C. 112(a) and 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, first and second paragraphs. See Donaldson, 16 F.3d at 1195, 29 USPQ2d at 1850; In re Knowlton, 481 F.2d 1357, 1366, 178 USPQ 486, 493 (CCPA 1973).
Therefore, even if the claims are interpreted in the manner suggested by Applicant as covering only the hLA212 antibody of SEQ ID NO: 30 and 34 and equivalents thereof, the examiner does not agree with Applicant’s interpretation of the covered “equivalents” as including human antibodies, avian antibodies and antibody variants. Human antibodies, variant antibodies, or avian antibodies could not reasonably be considered to be “equivalents” of the hLA212 antibody of SEQ ID NO: 30 and 34, because it would require undue experimentation to even make them. In other words, a reasonable interpretation of “equivalents” would not include antibodies that require undue experimentation to produce.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-12 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. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed means for binding to domain 3 of human LAG-3.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See MPEP 2163.
The instant claims are directed to a method for producing a LAG-3 antibody comprising culturing a cell comprising a nucleic acid having a nucleotide sequence encoding the amino acid sequence of the antibody, wherein the anti-LAG-3 antibody comprises means for binding to domain 3 of human LAG-3 while allowing human LAG-3 to bind to human MHC-II and allowing human LAG-3 to exert human T cell suppression function. Thus, practicing the claimed method requires possession of the claimed nucleic acid encoding the claimed antibody with the claimed function. The specification discloses rat anti-human LAG-3 VH and VL sequences that bind to domain 3 of human LAG-3 having SEQ ID NO: 2/4, or 6/8, or 10/12, or 14/16 or 18/20 (or having CDR sequences therefrom in SEQ ID NO: 40-46, SEQ ID NO: 47-52, SEQ ID NO: 53-58, SEQ ID NO: 59-64, or SEQ ID NO: 65-70, or humanized VH and VL thereof in SEQ ID NO: 28 or 30 and SEQ IQ NO 32, 34, 36, 38, or 49). However, on pages 60-61the specification also discloses that antibodies of the invention can be a human anti-LAG-3 antibody consisting of human antibody heavy and light chains made derived from human antibody producing animals or from phage libraries of human antibody scFv. Likewise, the specification discloses that bird antibodies could be used. Thus, the specification contemplates human and bird VH/VL structures that perform the claimed function. However, these structures represent an enormous genus of different VH/VLs. Likewise, the specification contemplates structures having certain percent identity to the disclosed SEQ ID Nos. For example, the specification discloses that the invention encompasses CDR mutants of the above VH/VL sequences, VH and VL at least 80% identical to the above VH/VL, and VH/VL encoded by any nucleic acid sequence that hybridizes to a nucleic acid sequence encoding the above VH/VL (see pages 11-12, paragraph 135, 161-165, 187-193, and 236-241, in particular). This represents a huge genus of different amino acid sequences with, for example, different even in CDR residues.
The state of the art is such that the antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. While the heavy chain is the most diverse, light chains are also important for binding specificity of antibodies, and swapping light chains can change the antigen specificity of the antibody (see Townsend et al., 2016, pages 1-2, in particular). Furthermore, the light chain repertoire is extremely diverse being encoded by kappa and lambda gene segments, each with different V and J genes. For example, Townsend teaches analysis of 29,000 distinct light chains having significant differences in physiochemical properties. See also Janeway, which teaches that the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. For kappa light chains, there are approximately 40 functional V gene segments and five J gene segments, and thus potentially 200 different Vkappa regions. Janeway teaches that for lambda light chains, there are approximately 30 functional V lambda segments and four J gene segments yielding 12 possible V lambda regions, so in all 320 different light chains can be make as a result of combination different light chain gene segments. These can also be further varied by a process of somatic hyper mutation. Furthermore, the diversity of the immunoglobulin repertoire is mediated in part by different combination so heavy and light chain V regions that pair to form a unique antibody binding site. See, for example, Rabia, 2018, which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4). Furthermore, the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Hall, 1992, Chen, 1992, and Rabia, 2018). The specification does not provide a correlation between structure and function for the genus of binding means encompassed by the instant claims. The specification discloses certain rat VH/VL amino acid sequences as well as certain humanized variants thereof (with the same CDRs). However, these are not sufficiently are not sufficiently representative of the claimed genus.
The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of antibodies and inhibitors encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See 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.)
The specification discloses that antibodies that perform the claimed function can be identified by screening assays. However, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
Given the claimed broadly class of antibodies, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making antibodies with the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Applicant argues that the claims are adequately described for the reasons set forth above.
The claims stand rejected for the same reasons set forth above.
Claims 1-12 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, in re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
“The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03)” The MPEP further states that physiological activity can be considered inherently unpredictable.
The instant claims are directed to a method for producing a LAG-3 antibody comprising culturing a cell comprising a nucleic acid having a nucleotide sequence encoding the amino acid sequence of the antibody, wherein the anti-LAG-3 antibody comprises means for binding to domain 3 of human LAG-3 while allowing human LAG-3 to bind to human MHC-II and allowing human LAG-3 to exert human T cell suppression function. Thus, practicing the claimed method requires the claimed nucleic acid encoding the claimed antibody with the claimed function. The specification discloses rat anti-human LAG-3 VH and VL sequences that bind to domain 3 of human LAG-3 having SEQ ID NO: 2/4, or 6/8, or 10/12, or 14/16 or 18/20 (or having CDR sequences therefrom in SEQ ID NO: 40-46, SEQ ID NO: 47-52, SEQ ID NO: 53-58, SEQ ID NO: 59-64, or SEQ ID NO: 65-70, or humanized VH and VL thereof in SEQ ID NO: 28 or 30 and SEQ IQ NO 32, 34, 36, 38, or 49). However, on pages 60-61, the specification also discloses that antibodies of the invention can be a human anti-LAG-3 antibody consisting of human antibody heavy and light chains made derived from human antibody producing animals or from phage libraries of human antibody scFv. Likewise, the specification discloses that bird antibodies could be used. Thus, the specification contemplates human and bird VH/VL structures that perform the claimed function. However, these structures represent an enormous genus of different VH/VLs. Likewise, the specification contemplates structures having certain percent identity to the disclosed SEQ ID Nos. For example, the specification discloses that the invention encompasses CDR mutants of the above VH/VL sequences, VH and VL at least 80% identical to the above VH/VL, and VH/VL encoded by any nucleic acid sequence that hybridizes to a nucleic acid sequence encoding the above VH/VL (see pages 11-12, paragraph 135, 161-165, 187-193, and 236-241, in particular). This represents a huge genus of different amino acid sequences with, for example, with different CDR residues. The specification does not provide any guidance regarding what specific structural features are required for achieving the claimed function.
The state of the art is such that the antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. While the heavy chain is the most diverse, light chains are also important for binding specificity of antibodies, and swapping light chains can change the antigen specificity of the antibody (see Townsend et al., 2016, pages 1-2, in particular). Furthermore, the light chain repertoire is extremely diverse being encoded by kappa and lambda gene segments, each with different V and J genes. For example, Townsend teaches analysis of 29,000 distinct light chains having significant differences in physiochemical properties. See also Janeway, which teaches that the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. For kappa light chains, there are approximately 40 functional V gene segments and five J gene segments, and thus potentially 200 different Vkappa regions. Janeway teaches that for lambda light chains, there are approximately 30 functional V lambda segments and four J gene segments yielding 12 possible V lambda regions, so in all 320 different light chains can be make as a result of combination different light chain gene segments. These can also be further varied by a process of somatic hyper mutation. Furthermore, the diversity of the immunoglobulin repertoire is mediated in part by different combination so heavy and light chain V regions that pair to form a unique antibody binding site. See, for example, Rabia, 2018, which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4). Furthermore, the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Hall, 1992, and Rabia, 2018). Thus, the state of the art is such that identifying antibody structures that function as claimed would be highly unpredictable.
Thus, based on the breadth of the claims and the unpredictability of the art, the instant specification must provide a sufficient and enabling disclosure, commensurate in scope with the instant claims. The instant specification exemplifies rat antibodies that bind to domain 3 of human LAG-3, and humanized versions thereof having specific CDR or VH/VL sequences, as noted above. The specification provides no guidance, for example, regarding which changes could be made to those antibodies, including in the CDR residues, while providing for the claimed functions. The specification discloses screening assays that can be used to identify human antibodies, for example, with the claimed function. However, no guidance is provided regarding any structural features of said claimed human antibodies. Given the diversity of the human antibody repertoire, making human binding means would require a trial and error process with no expectation that any particular binding means would function as claimed. Similarly, identifying CDR mutants of the disclosed VH/VL sequences would also require a similar trial and error process with not expectation that any particular mutation would retain function. This amounts to little more than two research assignments which would be highly unpredictable given the current state of the art. See Amgen Inc. v. Sanofi, 598 U.S. 594 (2023). Thus, based on the breadth of the claims, the unpredictability of the art, and the lack of guidance provided by the instant specification, it would require undue experimentation to make and use the binding means as broadly claimed.
Applicant’s arguments filed 11/6/25 have been fully considered, but they are not persuasive.
Applicant argues that the instant specification describes detailed functional assays that demonstrate the functions of these antibodies, and that using molecular biology methods one of ordinary skill in the art could produce the claimed antibodies using routine screening.
Applicant cites no evidence and merely provides attorney argument. Furthermore, Applicant essentially argues that through a trial and error screening process one could identify antibodies structures that meet the claimed function, thus satisfying the enablement requirement. However, this amounts to little more than a research assignment and would be highly unpredictable given the current state of the art. See Amgen Inc. v. Sanofi, 598 U.S. 594 (2023). T
Claims 1-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/898,463 in view of 20070134249 and US 20140004121.
The ‘463 application claims an anti-LAG-3 antibody comprising means for binding domain 3 of human LAG-3 while allowing human LAG-3 to bind to human MHC-II and allowing LAG-3 to exert human T cell suppression. The ‘463 application discloses identical structures (VH/VL sequences) as those disclosed by the instant specification. The ‘463 application claims that the antibody has an Fc region having ADCC activity. The ‘463 application claims that the antibody is a low fucose form, is humanized, chimeric and lacks a glycine and lysine residue at the carboxy terminus, and is obtained by a method comprising culturing a cell that comprises a nucleic acid molecule having a nucleotide sequence encoding the antibody, wherein the cell is a CHO cell. Although the ’463 application does not explicitly claim collecting the antibody and purification by affinity chromatography, it would be obvious to do so, since these are well known methodologies for antibody production, as taught by the ‘249 and ‘121 publications.
This is a provisional nonstatutory double patenting rejection.
Applicant’s statement that the rejection be held in abeyance until allowance is acknowledged.
No claim is allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644