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 .
DETAILED ACTION
Claims 1-11, 14, 17-22, 24-25, 27, 29-34, 39 and 43 are pending in the application and are under examination.
Claim Objections
Claim 29 is objected to for reciting Tables 30-33. MPEP 2173.05(s) states:
“Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
In this case, the sequences that the Tables refer to could easily be incorporated into the claim to define the invention as evidenced by the claims that additionally recite SEQ ID NOs. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-11, 14, 17, 19, 21, 24 and 29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The teachings of the specification and the claimed invention:
The nature and scope of the claimed invention at issue is a genus of IL-2 receptor binding proteins that bind IL2Rβ and IL2Rγ comprising VHH antibodies that comprise CDR sequences as set forth in the claims which can vary in up to 3 positions (see e.g., claim 2) or VHH antibodies that can comprise variable CDR sequences because of 90% identical language (see e.g., claim 17) or that can have CDRs mixed and matched from different antibodies (see e.g., claim 29).
The specification discloses in example 1 starting at page 146 that single domain antibodies (sdAbs, VHHs) were obtained from camels that bind antigens via screening assays. The antibodies that bind to IL2Rβ and IL2Rγ were described examples 3 and 4 and further characterized in other examples. The specification further discloses the sequences of the 3 CDRs from the VHH antibodies that bind IL2Rβ and IL2Rγ in multiple Tables.
However, the specification does not disclose making variations of any CDR or switching CDRs which would bind to IL2Rβ or IL2Rγ. Notably, as evidenced by Table 1 starting on page 41, the CDR1, CDR2 and CDR3 of each of antibodies that bind to IL2Rβ, differs greatly in amino acid sequence, respectively (see part of Table 1 copied below).
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519
757
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Similarly, as evidenced by Table 2 starting on page 44, the CDR1, CDR2 and CDR3 of each of antibodies that bind to IL2Rγ, differs greatly in amino acid sequence, respectively (see part of Table 3 copied below).
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760
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State of the Art
It is well established in the art that VHH antibodies comprise 3 CDRs involved in antigen binding and these CDRs are variable regions that occur as a result of gene recombination during selection of the antibody to bind an antigen (see Muyldermans et al (ARB:82:775-97, 2013, entire document, e.g., 777-780). There is no evidence in the art or the specification that a CDR from one antibody clone selected independently and which has a widely different sequence from another independent clone can be switched into a different antibody clone and retain binding.
The teachings from Muyldermans et al highlight that a skill artisan cannot recognize or predict that a CDR from one VHH can be switched into a different VHH and retain binding.
Claim Analysis
The instant claims encompass a subgenus of antibodies where CDRs from multiple independent clones are mixed into a single VHH and/or further varied in the CDR sequence and have a specific function (i.e. bind to IL2Rβ or IL2Rγ).
A skilled artisan would recognize that the specificity of a VHH is dependent upon its three specific CDR sequences. The instant specification discloses independent clones that sufficient for antigen-binding specificity to IL2Rβ or IL2Rγ, but do not identify a mixing CDRs from the independent clones and binding IL2Rβ or IL2Rγ or varying the CDR sequences and binding IL2Rβ or IL2Rγ.
As discussed above, VHH antibodies comprise 3 CDRs involved in antigen binding and these CDRs are variable regions that occur as a result of gene recombination during selection of the antibody to bind an antigen, but one cannot envision which (if any) mixed set of CDRs will bind to IL2Rβ or IL2Rγ or which CDR residues can be altered to bind IL2Rβ or IL2Rγ. It is noted that, “[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added). In this case, a skilled artisan cannot visualize CDRs in a VHH would bind to IL2Rβ or IL2Rγ other than the sets of 3 CDRs from the independent clones.
The disclosure therefore does not show that applicant was in possession of the necessary common attributes or features possessed by the members of the claimed genus. Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
Improper Markush Grouping
Claims 2-11, 14, 17, 19, 21, 24 and 29 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980), Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984) (Federal Register; Vol. 76, No. 27, Page 7166, February 9, 2011). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
The claims encompass multiple independent clones that bind to IL2Rβ or IL2Rγ. Notably, claim 29 recites 44 independent clones that bind to IL2Rβ and 44 independent clones that bind to IL2Rγ.
As evidenced by Muyldermans (supra) the antigen-combining site of a VHH antibody is a three-dimensional structure, which fully comprises three “complementarity-determining regions” (CDRs), which determine much of antibody's antigen-binding specificity. Accordingly, the substantial structural feature of a VHH antibody is the three CDRs of the antibody which determine much of antibody's antigen-binding specificity. Consequently, every antibody with different CDR sequences has a different substantial structural feature because different amino acids in the binding domains would bind to IL2Rβ or IL2Rγ. Therefore, because the Markush Groups in the claims each recite single domain antibodies with CDR sequences from different clones which differ in amino acid sequence and structure responsible for binding IL2Rβ or IL2Rγ and the antibodies otherwise do not appear to contain any substantial structural feature, it is submitted that the members of the Markush groupings do not share a substantial structural feature as required. For example, CDR3 of antibody DR214 (SEQ ID NO:3) and CDR3 of antibody DR217 (SEQ ID NO:7) only share 21.8% identity and have very different sequences (see alignment). Accordingly, the Markush groups do not share a substantial structural feature and are improper for that reason.
Title: US-18-260-709-3
Perfect score: 71
Sequence: 1 VDERCEAEDQIDY 13
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 10 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 1 summaries
Database : US-18-260-709-7.pep:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 15.5 21.8 10 1 US-18-260-709-7 COMPOSITIONS AND M
ALIGNMENTS
RESULT 1
US-18-260-709-7
Query Match 21.8%; Score 15.5; DB 1; Length 10;
Best Local Similarity 44.4%;
Matches 4; Conservative 3; Mismatches 1; Indels 1; Gaps 1;
Qy 6 EAED-QIDY 13
:|:| |:|
Db 2 DAQDAAIEY 10
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
In this case, it is suggested that Applicant amend the claims to remove multiple independent clones from the claims to obviate this rejection. Applicant is invited to submit new claims that are drawn to independent claims that recite bispecific binding proteins that bind IL2Rβ and IL2Rγ that recite one clone which binds to IL2Rβ and one clone that binds IL2Rγ, if so desired.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless -
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 18, 20, 22, 25, 27, 30-34, 39 and 43 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang et al (EP 3428193 B1, 2020).
With respect to claims 1, 22 and 25, Wang et al disclose an IL2 receptor (IL2R) binding protein that specifically binds to IL2R3 and IL2Ry, comprising an anti-IL2Rβ VHH antibody and an anti-IL2Rγ VHH antibody which can further comprise an Fc (see page 3, ¶10, (a bispecific antibody that binds IL2Rβ(CD122) and IL2Rγ (common gamma chain or CD132) and page 15, ¶111, wherein the bispecific antibody is a tandem VHH i.e., two VHHs linked by a linker and comprise a bispecific fusion protein with an Fc). With respect to claims 18 and 20, while Wang et al do not expressly teach an order of the two VHHs linked by a linker, one would at once envisage that the genus of tandem VHHs bispecific antibodies include one where the IL2Rβ antibody is at the N-terminus and another where the IL2Rγ antibody is at the N-terminus, so here the genus of Wang et al anticipates these two species (see MPEP § 2131.02).
With respect to claim 27, Wang et al disclose that the antibody can be conjugated to a drug including a PEG conjugate (i.e., the antibody is PEGylated) (see page 9, ¶ 60, page 10, ¶ 81 and page 26, ¶ 238). With respect to claims 30-32, Wang et al disclose nucleic acids in vectors encoding the antibody and such vectors in cells (see page 9). With respect to claim 33, Wang et al disclose the antibody in a pharmaceutical composition comprising a carrier (see page 23). With respect to claims 34, 39 and 43, Wang et al disclose treating cancer and viral infections and stimulating proliferation of T cells over other cells by administering the bispecific antibody (see pages 22 and 25).
Therefore, Wang et al is deemed to anticipate the instant claims absent a showing otherwise.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4-11, 14, 17-22, 24-25, 27, 29-34, 39 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (EP 3428193 B1, 2020), Kastelein et al (WO 2022/032006 A2, IDS) and Vivona et al (WO 2022/032884 A2, IDS)
Wang et al teach that which is set forth above. Wang et al do not disclose VHH antibody sequences encompassed by claims 4-11, 14, 17, 19, 21, 24 and 29.
Kastelein et al disclose the VHH sequences and CDR sequences of VHH antibodies that bind to IL2Rβ as set forth in instant claims 4-11, 14 and 29 (partial) in Table 1 at pages 5 and 6. Kastelein et al disclose that the antibody can be linked to another antibody in a bispecific antibody format at page 57.
Vivona et al disclose the VHH sequences and CDR sequences of VHH antibodies that bind to IL2Rγ as set forth in instant claims 4-11, 17 and 29 (partial) in Table 1 at pages 4-6. Vivona et al disclose that the antibody can be linked to another antibody in a bispecific antibody format at page 56.
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time the claimed invention was made to generate antibodies encompassed by claims 4-11, 14, 17, 19, 21, 24 and 29 by linking the VHH antibodies of Kastelein et al and Vivona et al in a tandem VHH antibody of Wang et al because the VHH antibodies of Kastelein et al and Vivona et al were art known and characterized VHH antibodies that could be predictably used in tandem VHH IL2Rβ and IL2Rγ bispecific antibodies. One would have been motivated to do so because generating such a tandem VHH could be made without difficulty, by routine steps, and with every expectation of success, such it would have been expected to bind both IL2Rβ and IL2Rγ. Making such tandem VHHs would be seen as combining prior art elements according to known methods to yield predictable results and simple substitution of one known element for another to obtain predictable results. Furthermore, the sequences of claims 19, 21 and 24 recite 90% identity language and as the prior art taught the VHH sequences, when the VHH antibodies of Kastelein et al and Vivona et al were constructed in the tandem VHH format the resulting proteins would be at least 90% identical to sequences in these claims because the sequences in these claims comprises the samer VHH sequences of Kastelein et al and Vivona et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 18, 20, 22, 25, 27, 30-34, 39 and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 9, 10, 17, 19-31 of copending Application No. 18/799,473. Although the claims at issue are not identical, they are not patentably distinct from each other.
Co-pending claims 1-11, 14, 17-22, and 24-27 are directed to IL2 receptor (IL2R) binding proteins that specifically bind to IL2Rβ and IL2Rγ comprising an anti-IL2Rβ VHH antibody and an anti-IL2Rγ VHH antibody (see co-pending claim 1). Then the other co-pending claims recite antibodies, nucleic acids and methods that anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
January 7, 2026