DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment, filed on 8/15/2022, is acknowledged.
Claims 14, 15, 20, and 23-25 have been cancelled.
Claims 1-13, 16-19, 21, 22, and 26 are currently pending.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 1-12 and 17, directed to an anti-CD22 antibody, and the species of clone EP97-G05, filed on 8/27/2025, is acknowledged.
Claims 13, 16, 18, 19, 21, 22, and 26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Claims 1-12 and 17 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed U.S. Provisional Patent Application No. 62/889,739, filed August 21, 2019, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/02/2022, 07/18/2023, 08/27/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner in its entirety.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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 1 and 3 are objected to because of the following informalities:
Claim 1 recites the antibody clone “EP35-A 7”, and should most likely recite “EP35-A7”, as disclosed by the specification on pg. 1, line 27,
Claim 3 recites “LC CD Rs” on lines 3 and 5, and most likely should be amended to recite “LC CDRs” to remove minor typographical errors.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-12 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing 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.
It is apparent that the hybridomas that produce the EP35-A7, EP35-B05, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-F01, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02 antibodies are required to practice the claimed invention. As required elements, these must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, a deposit of the hybridoma, which produces this antibody, may satisfy 35 U.S.C. 112(a). See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the hybridoma has been deposited under the Budapest Treaty and that the hybridoma will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the hybridoma described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
Claims 1-6, 9-11, and 17 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 claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claims 1, 5, 6, 9-11, and 17 encompass a broad genus of anti-CD22 antibodies with no recited structure and the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is selected from the group consisting of EP35-A7, EP35-B05, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02”.
Claim 2 encompasses a broad genus of antibodies with the same HCDR1-3 as the reference antibodies recited in claim 1 with up to 20% sequence variation and/or the same LCDR1-3 as the reference antibodies recited in claim 1 with up to 20% sequence variation, all with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1.
Claim 3 encompasses a broad genus of antibodies with the same HCDR1-3 as the reference antibodies recited in claim 1 with up to 8 amino acid residue variations and/or the same LCDR1-3 as the reference antibodies recited in claim 1 with up to 8 amino acid residue variations, all with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1.
Claim 4 encompasses a broad genus of antibodies with the same VH as the reference antibodies recited in claim 1 with up to 15% sequence variation and/or the same VL as the reference antibodies recited in claim 1 with up to 15% sequence variation, all with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1.
Claims 1, 5, 6, 9-11, and 17:
Claims 1, 5, 6, 9-11, and 17 require anti-CD22 antibodies that “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1 with no recited structure (i.e., amino acid sequence, especially in the CDRs critical for antigen binding). While the amino acid sequence of CD22 was known, immunizing an animal or screening a combinatorial library for clones that bind to CD22 will generate antibodies directed to a number of different epitopes within CD22 and not necessarily to the same epitope which is bound by the claimed reference antibodies recited in claim 1. The knowledge of the amino acid sequence of CD22, by itself, did not put Applicants in possession of antibodies that compete for binding with claimed anti-CD22 antibodies.
In determining that the Specification did not support the claimed anti-CD22 antibodies, the Specification disclosure is considered. The specification fails to disclose a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. Two of these factors described in the Specification was "a functional recitation of competing for binding" (pg. 15, lines 13-15 and pg. 43-44) and “structure of an epitope” (in general on pg. 15, lines 3-13 and for CD22 on pg. 5, lines 21-28). Thus, the skilled artisan could not envision the detailed chemical structure of the encompassed genus of antibodies until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Absent a recitation of distinguishing identifying characteristics, the Specification does not provide adequate written description support of the claimed genus.
The Federal Circuit has recognized that "the written description requirement can in some cases be satisfied by functional description," it has made clear that "such functional description can be sufficient only if there is also a structure-function relationship known to those of ordinary skill in the art." In re Wallach, 378 F.3d 1330, 1335 (Fed. Cir. 2004); see also, Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 964 (Fed. Cir. 2002) (holding that the written description requirement would be satisfied "if the functional characteristic of preferential binding ... were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed"); Amgen Inc. v. Sanofi, 782 F.3d 1367, 1378 (Fed. Cir. 2017) (holding that an "adequate written description must contain enough information about the actual makeup of the claimed products"). Here, the specification provides a functional description of the claimed antibody- i.e., that it competes for binding to the anti-CD22 antibodies recited in the claim, but the specification does not identify any disclosure of a correlation between the claimed function and the structure of the antibodies that perform that function.
Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed encoded anti-CD22 antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
For instance, citing to Centocor, the Court analogized an antigen and antibody to a lock and a key. For an antigen where there is only a finite number of binding antibodies, discovering those antibodies may be routine and conventional, and description of the antigen alone may be sufficient. By contrast, for antigens with millions of keys, or millions of potentially binding antibodies, description of the antigen and even a couple of examples may be far from sufficient.
This case is thus similar to Centocor Ortho Biotech, Inc. v. Abbott Laboratories, 636 F.3d 1341 (Fed. Cir. 2011). In Centocor, patentee claimed an antibody or antibody fragment that competitively inhibits binding of A2 (a mouse antibody) and that binds an epitope of TNF-α with a specified affinity. 636 F.3d at 1346. Both TNF-α protein and antibodies to that protein were known in the literature. Id. at 1352. Patentee argued that the patent at issue satisfied the written description for the claimed antibodies because it "not only describes the antibodies by their binding affinity for TNF-α, but further describes the antibodies by specifying that they competitively inhibit binding of the A2 mouse antibody to TNF-α." Id. At 1349. The Federal Circuit rejected this argument, finding that "[a]t bottom, the asserted claims constitute a wish list of properties that a fully-human, therapeutic TNF-α antibody should have: high affinity, neutralizing activity, and the ability to bind in the same place as the mouse A2 antibody." Id. At 1351. The court explained that "[t]he specification at best describes a plan for making fully-human antibodies and then identifying those that satisfy the claim limitations."
In finding that the specification at issue did not provide written description support for the claimed antibodies, the Centocor court recognized that the written description does not require examples or an actual reduction to practice, but clarified that "it does demand ... that one of skill in the art can 'visualize or recognize' the claimed antibodies based on the specification's disclosure." Id. at 1353. "In other words, the specification must demonstrate constructive possession." Id; see also, AbbVie Deutschland GmbH & Co., KG., v. Janssen Biotech, Inc., 759 F.3d 1285, 1301 (Fed. Cir. 2014) (reiterating requirement for structure-function correlation in functionally defined claims and finding that the patents at issue do not meet the written description requirement because they "do not describe any common structural features of the claimed antibodies.").
Here, as in Centocor, Applicant seeks to ground written description support for a claimed antibody in its competitive inhibition of another antibody (here, the monoclonal antibodies EP35-A7, EP35-B05, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02; in Centocor, mouse A2 antibody) and in the description of a known antigen (here CD22, in Centocor, TNF-α). While the state of the art has progressed since the Federal Circuit's decision in Centocor, the basic problem remains that the description at issue must allow one of skill in the art to "visualize or recognize" the claimed antibodies. Here, the evidence of record does not support that the skilled artisan would have visualized or recognized the claimed antibodies based on the description provided. As in Centocor, the Specification provides only a plan for identifying the claimed antibodies.
Claims 2-4:
Claims 2-4 encompass genera of anti-CD22 antibodies that have either the same HCDRs and/or LCDRs as the antibodies recited in claim 1 and with up to 20% sequence variation in each of the light and heavy chain CDRs (claim 2), up to 8 amino acids substituted in each of the light and/or heavy chain CDRs (claim 3), or with the same VH and/or VL as the reference antibodies recited in claim 1 but with up to 15% sequence variation, including in the CDR regions (claim 4), all with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural features that provide the recited functions of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is selected from the group consisting of EP35-A7, EP35-B05, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02”. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or U.S.C 112, ¶ 1 "Written Description" Requirement make clear that 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 genus.
The specification discloses construction of human scFv libraries comprising 1012-13 scFv antibodies (pg. 39, lines 20-23): “[a] single-chain antibody (scFv) library was then constructed by VH and VL shuffling. The library size is predicted to be 1012-13.” The libraries were screened in multiple rounds to identify scFv clones that specifically binds to CD22 (pg. 40, lines 3-6 and Figure 1): “At round 3, enriched VH library was converted to scFv library by shuffling with a naive VL library noted above and further enriched for 3 more rounds. A total of 4 rounds of selections was executed to generate highly enriched anti-CD22 antibody pools…”.
20 scFv clones were identified that specifically bound to CD22, which are clones EP35-A7, EP35-B5, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02 (Figure 2, Tables 1 and 4, SEQ ID NO: 3-59).
The specification fails to provide adequate written description support for a genus of antibodies having the desired functional properties required to practice the claimed functions of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is selected from the group consisting of EP35-A7, EP35-B05, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02”.
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [ of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
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." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species." Id.
"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" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The specification only discloses a limited number of antibody structures, EP35-A7, EP35-B5, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02, within the claimed genera of antibodies with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is selected from the group consisting of EP35-A7, EP35-B05, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02”, which do not represent the broadly claimed genera of antibody structures, defined by their amino acid sequences especially in the CDR regions critical for binding, encompassed by the instant claims.
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
A representative number of species means that the species which are adequately described are representative of the entire 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. A "representative number of species" means that the species which are adequately described are representative of the entire 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. See Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
The claims are directed to a genus of anti-CD22 antibodies with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-CD22 antibodies to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the claimed broadly class of antibodies and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed class of antibodies with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1, 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), MPEP 2163.
The specification at best describes plan for making antibodies that bind the same epitope as or competes with the anti-CD22 antibody clones recited in claim 1, but a mere “wish or plan” for obtaining the claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
The specification discloses a limited number of anti-CD22 antibodies – EP160-C07, EP160-E03, EP97-A10, EP97-B03, EP160-D02, EP160-G04, EP160-H02, EP160-G05, EP35-C6, EP35-A7, EP35-D6, EP35-E6, EP35-C8, EP160-F04, EP35-B05, EP97-G05, EP97-F01, and EP97-A01 – which were not random combinations of VH and VL; i.e., they had specific VH domains (SEQ ID NO: 3, 5, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, and 38, respectively) paired with specific VL domains (SEQ ID NO: 4, 6, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 39, respectively). The specification further discloses scFv versions of these antibodies, including EP97-A10 (SEQ ID NO: 40-59). The specification also discloses one single domain antibody with this recited function, EP160-F10 (SEQ ID NO: 7).
The specification discloses only 20 antibodies within the instant claim scope. Claims 2 of the instant application encompasses (but does not exemplify) fragments and CDR modifications up to 20% (deletion/addition/substitution) to the claimed HCDRs and/or LCDRs of the antibody clones recited in instant claim 1, and claim 3 of the instant application encompasses (but do not exemplify) CDR substitutions of up to 16 amino acids per set of 6 CDRs. Claim 4 of the instant application encompasses up to 15% variation in the entire VH and/or VL of the antibody clones recited in instant claim 1, which includes significant variation in the CDRs. However, there is no teaching identifying what amino acids can be varied within the VH-CDRs or VL-CDRs antibody regions and still retain antibody or fragments capable of specifically binding to PCSK9. Brown et al. (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. The scope of the claims encompasses antibodies with VH or VL that encompass variation (additions, deletions, substitutions) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g., 6CDRs) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds PCSK9 to satisfy the WD requirement for the claims.
It is unlikely that antibodies or fragments thereof as defined by the claims which may contain less than the full complement of CDRs from the heavy and light chain variable regions of the reference antibodies recited in claim 1 fused to framework sequences have the required binding function. The specification provides no direction or guidance regarding how to produce monoclonal antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone. Further, the specification does not teach that a functional antibody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 6 CDRs sequences of a donor antibody.
With respect to the recitation of an antibody with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1 which does not comprise all 6 CDRs of the antibody, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ( https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Absent any teaching of structure-function relationships, the skilled in the art cannot determine the critical amino acids in the CDR in the recited sequences and also possess the recited function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1. See AbbVie Deutschland GmbH v. Janssen Biotech, Inc. (Fed. Cir. 2014).
The facts of AbbVie parallel the claimed invention and provide significant guidance on the inherent unpredictability of protein engineering and the effect of amino acid substitutions on protein function. Abbvie is similar to the Federal Circuit's discussion in Novozymes A/S et al. v. Dupont Nutrition Biosciences APS et al., 2013 WL 3779376, Case No. 2012-1433, C.A.Fed; in both, the Federal Circuit emphasized the unpredictability in the art associated with changes in a parent enzyme or protein that can be affected at one or more positions in the sequence by amino acid addition, deletion, or substitution with at least nineteen other possibilities, e.g., counting natural amino acid residues. The basis of the unpredictability is rooted in the same principles that make improvements rare, namely that numerous subtle differences between amino acid residues determine protein binding and function. Because the subtle energetic contributions of each of these interactions is extraordinarily difficult to precisely quantify, and because the number of these interactions is so high even for a single protein-protein interface, innumerable small inaccuracies are amplified into unpredictability. This unpredictability is axiomatic in the field of protein engineering.
For example, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 ("[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology."); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity. Moreover, the '128 and '485 patents of AbbVie do not describe any common structural features of the claimed antibodies. The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of anti-TMPRSS6 antibodies or antigen binding fragments thereof falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 1-6, 9-11, and 17 do not meet the requirements of 35 U.S.C. 112(a) for written description.
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.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed
Claims 1-6, 9-11, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for antibodies with the HCDR1-3 and LCDR1-3 and/or the VH and VL of the antibody clones, or the VHH if the clone is a single domain antibody, recited in claim 1, does not reasonably provide enablement for a large class of antibodies with no recited structure (claims 1, 5, 6, 9-11, and 17) or a partial structure at best (claims 2-4) and the recited function “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Breadth of claims and nature of invention:
Claims 1, 5, 6, 9-11, and 17 encompass a broad genus of anti-CD22 antibodies with no recited structure and the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is selected from the group consisting of EP35-A7, EP35-B05, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02”, which includes a vast quantity of antibody structures with the recited function.
Claims 2-4 encompass genera of anti-CD22 antibodies that have either the same HCDRs and/or LCDRs as the antibodies recited in claim 1 and with up to 20% sequence variation in each of the light and heavy chain CDRs (claim 2) or up to 8 amino acids substituted in each of the light and heavy chain CDRs (claim 3), or with the same VH and/or VL as the reference antibodies recited in claim 1 but with up to 15% sequence variation, including in the CDR regions (claim 4), all with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1. Each of these claims recite a broad class of antibody structures with a partial structure at best with the recited function, which includes a vast quantity of antibody structures.
The specification discloses screening human scFv libraries of up to 1012-13 antibodies for clones that bind to CD22 (pg. 39-40, Figure 1). A total of four rounds of selection were conducted to generate antibody clones that were specific for CD22 (Figure 1). 20 clones were identified that has a high affinity for CD22 (Table 1, Figure 3).
Amount of direction and existence of working examples:
The specification discloses 20 examples of different anti-CD22 antibodies in Table 1, with their VH/VL sequences recited in SEQ ID NO: 3-39 (pg. 11-14). The scFv sequences of the antibodies are disclosed in SEQ ID NO: 40-59 (pg. 17 and 18).
Level of predictability, state of prior art, and quantity of experimentation needed:
The claims are directed to a genus of antibodies with either no recited structure (claims 1, 5, 6, 9-11, and 17), or a partial structure at best that includes significant variation in the CDR regions of the antibody which are critical for antigen specificity (claims 2-4), with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1, which includes millions to billions of different antibodies with varying CDR sequences with the recited function.
However, the specification did not give the skilled in the art enough information to choose candidate antigen binding structures from the vast number of options of millions of candidates, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses multiple different examples of anti-CD22 clones with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1, which are the clones EP35-A7, EP35-B05, EP35-C6, EP35-C8, EP35-D6, EP35-E6, EP35-E7, EP97-A01, EP97-A10, EP97-B03, EP97-FO1, EP97-G05, EP160-C07, EP160-D02, EP160-E03, EP160-F04, EP160-F10, EP160-G04, EP160-G05, and EP160-H02.
These antibody clones, defined by their specific amino acid sequences, have a great deal of variation between their CDR regions. For example, clones EP160-C07 and EP160-E03 were both selected because of their specific binding to CD22 (Table 1). However, the VH sequences of these clones (SEQ ID NO: 3 and 5, respectively) have only 57.2% sequence identity, with 19 amino acid residue mismatches in the CDR regions (collectively the CDR regions, in bold, have 21.9% sequence identity):
Qy 1 QMQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNY 60
::|||||| | :|| |:::|| |||:||:|||: |||||||:||||: | | |
Db 1 EVQLVQSGGGVVQPGKSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYY 60
Qy 61 AQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAVAGSRGYWGQGTLVTVSS 118
| ::|| |:: | | :| |::: |||::|||||||||| | |||||| |||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGWTGF-DYWGQGTTVTVSS 117
The instant specification does not disclose any guidance on which amino acid sequence structures would predictably give rise to antibodies with the function of “binds to the same epitope as a reference antibody or competes against the reference antibody from binding to CD22, and wherein the reference antibody is” recited in claim 1.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their