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 6/23/2023, is acknowledged.
Claims 4 and 11 are cancelled
Claims 1-3, 5-10, and 12-16 are currently pending.
Claims 1 and 16 are independent claims
Election/Restrictions
Applicants’ election without traverse of the sdAb species with CDR1-3 of SEQ ID NO: 3, 6, and 9, respectively, and the VHH of SEQ ID NO: 19 and 32, filed on 3/23/2026, is acknowledged.
Claims 1-3, 5-10, and 12-16 are under examination as reading on a single domain antibody that binds to human CCR8 comprising the CDR1-3 of SEQ ID NO: 3, 6, and 9, respectively.
Priority
Applicant’s claim for the benefit of a prior-filed European Patent Application Serial No. 20217314.2, filed December 24, 2020, and European Patent Application Serial No. 21167247.2, filed April 7, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 6/23/2023 and 9/19/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
Specification
The use of the terms:
GIBCO™ (pg. 48, lines 25 and 27);
FUGENE® (pg. 48, line29);
Attune™ (pg. 49, line 1; pg. 53, line 22; pg. 57, line 30);
Affinipure® (pg. 51, line 30; pg. 55, line 3);
Superdex® (pg. 55, line 27; );
MidiTrap™ (pg. 56, line 15; );
which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at pg. 2, lines 15-16; pg. 13, line 26; and pg. 21, line 30. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 1-3 are objected to under 37 CFR 1.75(c) because it is improper dependent claim since it fails to refer back to an earlier claim. Rather claims 1-3 refer back to a proceeding claim 5. 37 CFR 1.75(c) states: (c) One or more claims may be presented in dependent form, referring back to and further limiting another claim or claims in the same application.
Claims 1-3 and 5 recite the acronym “hCCR8”. This is not a readily recognized acronym in the art, such as “DNA” for 5’-deoxyribonucleic acid. Please define the acronyms “hCCR8” when it is first used in the claims.
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 1-3, 5-7, 9, 10, and 12-16 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 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claims 1-3, 5-7, 9, 10, and 12-15 encompass a broad genus of sdAbs with a partial structure at best and the function of “binds to hCCR8”. For example, claims 1-3, 5, 7, 9, 10, and 12-15 recite a genus of sdAbs with only a defined CDR3 sequence and with either 80% variation or up to 3 amino acid substitutions in the CDR3 sequence, and claim 6 recites a genus of sdAbs with any combination of the recited CDR1-3 sequences and with either 80% variation or up to with up to 3 amino acid substitutions in the recite sequences. Claim 16 encompasses a genus of human CCR8 (hCCR8) binders comprising CDR1-3 selected from the respective CDR1, CDR2 and CDR3 comprised in the elected species of SEQ ID NO: 19 as defined by the Kabat, Chothia, AHo or IMGT information system.
However, the specification fails to provide adequate written description support for a genus of antibody heavy chain constant regions with no recited structure having the desired functional properties required to practice the claimed functions of “binds to hCCR8”.
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 discloses identification and selection of sdAb structures that specifically bind to human and murine CCR8 after screening for binding structure using phage display libraries (Example 1). The discloses identification of the following sdAb clones from the phage library screen that binds to hCCR8, which are VHH-57, VHH-64, VHH-67, VHH-84, VHH-119, VHH-120, VHH-121, and VHH-122 (SEQ ID NO: 31, 30, 32, and 17-21, respectively). Each of these sdAb clones are defined by their amino acid sequences, especially in the CDR1-3 regions that are critical for antigen binding, that give rise to the function of “binds to hCCR8”.
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 single domain antibodies with a partial structure at best and the function of “binds to hCCR8”. 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.
In the instant case, the instant specification discloses 8 sdAb structures with the claimed function of “binds to hCCR8”. No other representative species is disclosed that have the function of “binds to hCCR8”. This limited number of sdAb structures do not sufficiently represent the broad genera of antigen binding constructs with differing CDR sequences that are encompassed by the claims with the recited function of “binds to hCCR8”.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed sdAbs 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 broadly claimed class of sdAbs, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed class of antigen binding molecules that bind to a ligand, 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 sdAbs that have the recited function of “binds to hCCR8”, and then identifying those that satisfy the claim limitations, but a mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
The specification discloses only 8 sdAbs within the claimed scope, all of which are defined by their amino acid sequences, especially in the CDR regions that are critical for binding. 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 VHH domain of these 8 sdAb species fused to framework sequences have the required binding function. The specification provides no direction or guidance regarding how to produce sdAbs with the function of “binds to hCCR8” as broadly defined by the claims.
Neither the specification, nor the prior art provides any examples to support the premise of mixing and matching the CDRs of different sdAbs would result in antigen binding. The prior art does not support a definition of an antibody structure by mixing and matching the CDR1-3 sequences of a VHH domain would result in a functional anti-hCCR8 antibody. The specification fails to show that all CDR1, CDR2, and CDR3 of the anti-hCCR8 sdAbs VHH-57, VHH-64, VHH-67, VHH-84, VHH-119, VHH-120, VHH-121, and VHH-122, are equivalent. The specification fails to establish that by replacing at least one CDR of , for example, VHH-57 with another of VHH-64, VHH-67, VHH-84, VHH-119, VHH-120, VHH-121, or VHH-122 maintains specific hCCR8 binding. Mixing and matching different the CDRs from different anti-CCR8 sdAbs has not been shown to lead to specific CCR8 binding. Such teachings were not made part of the specification at the time the invention was made.
Claims 1-3, 5, 7, 9, 10, and 12-15 additionally encompass a genus of sdAbs with only a defined CDR3 sequence and with either 20% variation or up to 3 amino acid substitutions in the CDR3 sequence, and claim 6 encompasses a genus of sdAbs with any combination of the recited CDR1-3 sequences and with either 20% variation or up to with up to 3 amino acid substitutions in the recite sequences.
The specification discloses only 8 single-domain antibodies within the instant claim scope. However, the claims of the instant application encompass (but do not exemplify) fragments and CDR modifications up to 20% (deletion/addition/substitution), or up to 2 amino acid substitutions, to the claimed CDR regions. There is no teaching identifying what amino acids can be varied within the antibody CDR regions and still retain antibody or fragments capable of specifically binding to hCCR8. 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 VHH-57, VHH-64, VHH-67, VHH-84, VHH-119, VHH-120, VHH-121, and VHH-122 antibodies 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 3 CDRs sequences of a donor sdAb.
With respect to the recitation an antibody which does not comprise all 3CDRs of the antibody that is produced by VHH-57, VHH-64, VHH-67, VHH-84, VHH-119, VHH-120, VHH-121, and VHH-122, 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 (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. Here, given that the antibodies are single-domain antibodies, this would apply to the 3CDRs of the VHH chain.
Regarding the amino acid substations in variable regions, one skilled in the art would have recognized challenge and trade-offs once it is applied in antibody. Rabia et al. (Biochem Eng J. 2018 September 15; 137: 365-374) states that to optimize antibody properties (affinity, specificity, stability, solubility and effector functions) with amino acid substitutions is challenging and there is always trade-off. Rabia et al. further states that an outstanding challenge in the field is that optimizing properties such as antibody affinity can lead to defects in other properties such as antibody stability, specificity and solubility. The resulting trade-offs between improvements in some antibody properties and reductions in others highlight that they are often interdependent and cannot be easily separated (Introduction). Rabia et al. further state given that the maximal chemical diversity of antibody CDRs is unimaginably large (>1078 antibody variants based on 20 different amino acids at ~60 sites in the CDRs), it is extremely challenging to define the sequence determinants of antibody specificity (para 2).
While there are some publications which acknowledge that CDR3 is important, the conformations of other CDRs as well as framework residues influence binding. MacCallum et al. (J. Mol. Biol., 262, 732-745, 1996) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col.) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (Biochemical and Biophysical Research Communications, 307:198-205, 2003), which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.).
However, neither the specification, nor the prior art provides any examples to support the premise that CDR3 of a variable region (i.e., a VHH) is solely responsible for antigen binding. The prior art does not support a definition of an antibody structure solely by defining the CDR3 sequence of a variable region. Accordingly, the disclosed species would not be deemed by one of skill in the art to be representative of the claim scope.
Regarding claim 16, the claimed genus of single-domain antibody moiety recited in instant claims and the claimed genus of human CCR8 (hCCR8) binder recited in claim 16 are not limited to heavy chain variable domain (VHH) antibodies or VHH-Fc fusion proteins as shown in the Examples, but also encompass any single domain antibodies with no defined structure and function in view of the definition of “binder” as disclosed by the specification (pg. 7-8): “…the hCCR8 binder is antibody based or non-antibody based, preferably antibody based. Nonantibody based binders include, but are not limited to, affibodies, Kunitz domain peptides, monobodies (adnectins), anticalins, designed ankyrin repeat domains (DARPins), centyrins, fynomers, avimers; affilins; affitins, peptides…” Applicant has not shown adequate written description support for such a broadly claimed genus of binders, which includes, for example, DARPins comprising the elected CDRs with the claimed function of “binds to hCCR8”.
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 1-3, 5-7, 9, 10, and 12-16 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.
To resolve this issue, it is recommended to amend claim 5 to either: 1) recite the CDR combinations of each working example of anti-human CCR8 sdAb structure (for example, the elected CDR1-3 species of SEQ ID NO: 3, 6, and 9, respectively); 2) recite the full VHH sequences of each working example of anti-hCCR8 sdAb structure (i.e., the VHH sequences recited in instant claim 8; or both. Regarding claim 16, it is recommended to limit the claim to sdAbs comprising the recited CDRs to resolve this issue.
Claims 1-3, 5-7, 9, 10, and 12-16 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 sdAbs comprising the CDRs of the VHH-57, VHH-64, VHH-67, VHH-84, VHH-119, VHH-120, VHH-121, and VHH-122 with the function of “binds to human CCR8”, as well as methods of treating tumors comprising administration of these specific sdAb structures, does not reasonably provide enablement for a broad genus of sdAbs with a partial structure at best and the function of “binds to human CCR8”, or methods of treating cancer comprising administration of a broad genus of sdAbs with a partial structure at best and the function of “binds to human CCR8”. 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 1-3, 5-7, 9, 10, and 12-15 encompass a broad genus of sdAbs with a partial structure at best and the function of “binds to hCCR8”. For example, claims 1-3, 5, 7, 9, 10, and 12-15 recite a genus of sdAbs with only a defined CDR3 sequence and with either 80% variation or up to 3 amino acid substitutions in the CDR3 sequence, and claim 6 recites a genus of sdAbs with any combination of the recited CDR1-3 sequences and with either 80% variation or up to with up to 3 amino acid substitutions in the recite sequences.
For example, regarding claim 6 and the elected species of sdAb, the claim encompasses a genus of sdAbs with CDR1-3 of SEQ ID NO: 3, 6, and 9, respectively with 2 amino acid substitutions in each CDR. The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula:
N
!
*
19
A
N
-
A
!
A
!
Where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. For the CDRs of the elected species of antibody with 2allowed substitutions in each CDR, there would be
8
!
*
19
(
2
)
8
-
2
!
2
!
x
7
!
*
19
(
2
)
7
-
2
!
2
!
x
17
!
*
19
(
2
)
17
-
2
!
2
!
Which is approximately 2.8x1011 variants.
Claim 16 encompasses a genus of human CCR8 (hCCR8) binders comprising CDR1-3 selected from the respective CDR1, CDR2 and CDR3 comprised in the elected species of SEQ ID NO: 19 as defined by the Kabat, Chothia, AHo or IMGT information system.
The specification discloses identification and selection of sdAb structures that specifically bind to human and murine CCR8 after screening for binding structure using phage display libraries (Example 1).
Amount of direction and existence of working examples:
The instant specification discloses identification of the following sdAb clones from the phage library screen that binds to hCCR8, which are VHH-57, VHH-64, VHH-67, VHH-84, VHH-119, VHH-120, VHH-121, and VHH-122 (SEQ ID NO: 31, 30, 32, and 17-21, respectively). Each of these sdAb clones are defined by their amino acid sequences, especially in the CDR1-3 regions that are critical for antigen binding, that give rise to the function of “binds to hCCR8”.
The specification additionally discloses that VHH-Fc-205 (which comprises VHH-57) and VHH-Fv-215 (which comprises VHH-67) successfully bound CCR8 to inhibit immunosuppression via Tregs to lead to a decrease of tumor growth in a MC38 mouse tumor model (Example 12, Fig. 11).
Level of predictability, state of prior art, and quantity of experimentation needed:
Regarding claims 1-3, 5-7, 9, 10, and 12-15, the claims are directed to sdAbs, and methods of treatment comprising administration of sdAbs, with a partial structure at best, all with the function of “binds to hCCR8”, which includes broad genera of millions to billions of different sdAb structures with the recited function.
Regarding claim 16, the claim is directed to a genus of human CCR8 (hCCR8) binders that are not limited to heavy chain variable domain (VHH) antibodies in view of the definition of “binder” as disclosed by the specification (pg. 7-8): “…the hCCR8 binder is antibody based or non-antibody based, preferably antibody based. Nonantibody based binders include, but are not limited to, affibodies, Kunitz domain peptides, monobodies (adnectins), anticalins, designed ankyrin repeat domains (DARPins), centyrins, fynomers, avimers; affilins; affitins, peptides…” Applicant has not shown adequate written description support for such a broadly claimed genus of binders, which includes, for example, DARPins comprising the elected CDRs with the claimed function of “binds to hCCR8”.
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 8 different sdAb clone structures with the function of “binds to hCCR8”.
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 function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. 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 that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
In the instant case, the claims are directed to a broad class of single-domain antibodies, or methods of treatment comprising administration of sdAbs, with a partial structure at best and the function of “binds to hCCR8” (claims 1-3, 5-7, 9, 10, and 12-15), or a broad class of “binders” which include both antibody and nonantibody structures with the recited CDRs in claim 16.
Regarding claims 1-3, 5-7, 9, 10, and 12-15, the instant claims are directed to classes of sdAb structures that include “a ‘vast’ number” of additional structures (i.e., amino acid sequences of all of the CDR1-3 regions that are necessary for antigen binding) in which the instant specification fails to describe. It would be necessary to first generate and then screen each candidate single-domain antibody agent to determine whether or not it met the function limitations of “binds to hCCR8”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant specification does not disclose any common structural feature delineating which other polypeptide structures would have the function of “binds to hCCR8”. The only structure-function relationship guidance the specification provides is to disclose individual examples of anti-hCCR8 sdAb structures with these functions.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antibody structures they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
Applicant is relying upon certain biological activities such as inhibitory antibodies binding to CCR8 and a limited number of species with defined structures (e.g. amino acid sequences) to support an entire genus of diverse and structurally unrelated inhibitory polypeptide structures. Yet the instant specification does not provide sufficient guidance and directions as to the structural features of the polypeptide structures and the correlation between the structure and the desired antigen binding and inhibitory function.
Regarding claim 16, the claimed genus of single-domain antibody moiety recited in instant claims and the claimed genus of human CCR8 (hCCR8) binder recited in claim 16 are not limited to heavy chain variable domain (VHH) antibodies or VHH-Fc fusion proteins as shown in the Examples, but also encompass any single domain antibodies with no defined structure and function in view of the definition of “binder” as disclosed by the specification (pg. 7-8): “…the hCCR8 binder is antibody based or non-antibody based, preferably antibody based. Nonantibody based binders include, but are not limited to, affibodies, Kunitz domain peptides, monobodies (adnectins), anticalins, designed ankyrin repeat domains (DARPins), centyrins, fynomers, avimers; affilins; affitins, peptides…” Applicant has not shown adequate written description support for such a broadly claimed genus of binders, which includes, for example, DARPins comprising the elected CDRs with the claimed function of “binds to hCCR8”. Undue experimentation would be required by one with ordinary skill in the art to generate structures other that sdAb VHH structures comprising the recited CDRs that maintain the function of “binds to hCCR8”. It would be necessary to first generate and then screen each candidate nonantibody structure comprising the recited CDRs to determine whether or not it met the function limitations of “binds to hCCR8”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
Additionally, in its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be "materially indistinguishable from those in Amgen." Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers "millions of potential candidate antibodies" (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, "the '590 patent's roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose." (Id.) Missing from the specification, according to the Federal Circuit, was "'a quality common to every functional embodiment' ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions" (id.; quoting Amgen Inc. v. Sanofi., 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta's argument that its disclosed hybridoma-and screening process "predictably and reliably generates new claimed antibodies every time it is performed" (id.), because "it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions." (Id.).
The specification does not reasonably provide enablement to make and use the invention of instant claims 1-3, 5-7, 9, 10, and 12-16. The specification does enable one with ordinary skill to make the antibody clone discussed supra.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
To resolve this issue, it is recommended to amend claim 5 to either: 1) recite the CDR combinations of each working example of anti-human CCR8 sdAb structure (for example, the elected CDR1-3 species of SEQ ID NO: 3, 6, and 9, respectively); 2) recite the full VHH sequences of each working example of anti-hCCR8 sdAb structure (i.e., the VHH sequences recited in instant claim 8; or both. Regarding claim 16, it is recommended to limit the claim to sdAbs comprising the recited CDRs to resolve this issue.
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.
Claim 16 is 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 16 recites “a human CCR8 (hCCR8) binder”. It is currently unclear if this recited limitation refers to “a molecule binding to hCCR8” such as a sdAb or “a human molecule that binds to CCR8”, such as a human antibody that specifically binds to CCR8, rendering the claim indefinite. Additionally, it is unclear what the claimed human CCR8 binder is. The CDR1-3 are not defined and vary. Since the meters and bounds cannot be determine, a skilled artisan cannot envision what sequences the CDR1-3 are, and which human CCR8 binders are included within the scope of the claim. Thus, the claim is indefinite.
Conclusion
Claim 8 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
When all other issues are resolved, the search and examination will extend to the other unelected Species of the invention.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Lan et al. (Cancer Res (2020) 80 (16_Supplement): 6694 doi.org: 10.1158/1538-7445.AM2020-6694) teaches an anti-CCR8 inhibitory antibody BMS-968340 that targets CCR8 on Treg cells to decrease the immunosuppressive effect and enhance anti-tumor outcomes as a single agent an in combination with checkpoint inhibitors such as anti-PD-1 therapies (Results, Conclusion). However, Lan et al. does not teach anti-CCR8 therapeutic nanobodies with the elected species of CDR3.
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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