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
Applicant’s amendments and remarks filed on April 22, 2026 are acknowledged. Claims 3, 9, 11-14, 16-18, 20-22, 24-26, 28, 29, 31, 32, 35-38, 41, 42, 44, 45, 47, 49-53, 55, 56, 59-61, 63, and 65 have been canceled. Claims 1 and 15 were amended. Claim 64 was withdrawn. Claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, 64, and 66 are pending.
Claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66 are examined on the merits herein.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 22, 2026 has been entered.
Priority
This application claims priority to PCT/US2020/038475 filed on June 18, 2020 which claims priority to U.S. provisional application 62/864,755 filed on June 21, 2019.
Withdrawn Objections
In view of Applicant’s amendments and response, the objections to the specification and the claim objections are withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 103 and nonstatutory double patenting rejections are withdrawn.
Specification
The substitute specification filed on April 22, 2026 has been entered.
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.
Written Description
Claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 is drawn to a genus of second variable domains that comprise a reactive residue. The sequences recited in claim 1 parts (A) through (C) only specify the amino acid sequence of the first variable domain. The sequences in claim 1 part (D) specify the amino acid sequence of a first heavy chain, a second heavy chain, and a light chain. The specification discloses in paragraph [00241] that an immunoglobulin molecule comprises an additional chain wherein the first heavy chain comprises a first and second variable domain, the second heavy chain comprises a first and second variable domain, and the light chain comprises a variable domain and a constant domain. The specification discloses that the dual variable domain immunoglobulin molecule comprises a first variable domain that binds to a binding target and a second variable domain that comprises a reactive residue where the linker is covalently conjugated to the reactive residue [0008]. Therefore, the first and second variable domains must be specified by an amino acid sequence.
Claim 57 recites in part wherein the second variable domain of Ig comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9, 10, 11, 12, 13, 14, and any combinations thereof. SEQ ID NOS: 9, 11, and 13 refer to a light chain and SEQ ID NOS: 10, 12, and 14 refer to a heavy chain. The claim as currently written encompasses a second variable domain that comprises SEQ ID NOS: 9, 10, 11, 12, 13, or 14 in addition to combinations of any light chains (SEQ ID NOS: 9, 11, and 13) with any heavy chains (SEQ ID NOS: 10, 12, and 14).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
The specification discloses that a conjugate of the invention comprises a dual variable domain immunoglobulin molecule or an antigen-binding fragment thereof, and a double-stranded RNA molecule linked together via a linker. The dual variable domain immunoglobulin molecule comprises a first variable domain that binds to a binding target and a second variable domain that comprises a reactive residue where the linker is covalently conjugated to the reactive residue [0008]. The specification envisions that the amino acid sequences of a first variable domain region, which provides antigen binding functionality, can include chimeric, humanized, or human amino acid sequences. Further, any suitable combination of such sequences can be incorporated into a first variable domain of the DVD immunoglobulin molecule [00222]. The specification also envisions that the DVD immunoglobulin molecule comprises a second variable domain from a 38C2 antibody which includes a reactive lysine residue [00225]. The specification discloses in paragraphs [00254] through [00260] that the DVD immunoglobulin comprises SEQ ID NO: 18 and 19 that binds to CD138; SEQ ID NO: 20 and SEQ ID NO: 21 that binds to BCMA; SEQ ID NO: 22 and SEQ ID NO: 23 that binds to SLAMF7; SEQ ID NO: 24 and SEQ ID NO: 25 that binds to HER2, light chain and heavy chain, respectively. Paragraph [00261] discloses that the DVD immunoglobulin comprises SEQ ID NO: 28 (a first heavy chain), SEQ ID NO: 29 (a second heavy chain), and SEQ ID NO: 30 (a light chain). The specification discloses in paragraph [00241] that an immunoglobulin molecule comprises an additional chain wherein the first heavy chain comprises a first and second variable domain, the second heavy chain comprises a first and second variable domain, and the light chain comprises a variable domain and a constant domain.
The specification discloses that the dual variable domain immunoglobulin molecule comprises a first variable domain that binds to a target antigen and a second variable domain that includes uniquely reactive residues that provide a site for covalent attachment of a linker molecule. Further, the DVD immunoglobulin molecule includes two identical light chains as well as two identical heavy chains [00199]. SEQ ID NOS: 9, 11, and 13 refer to a light chain and SEQ ID NOS: 10, 12, and 14 refer to a heavy chain. The specification discloses that the DVD immunoglobulin molecule includes a light chain variable domain sequence of a humanized 38C2 antibody (SEQ ID NO: 9 and 15) and a heavy chain variable domain sequence of a humanized 38C2 antibody (SEQ ID NO: 10 and 16) [00234-00235]. No description is provided of any other combinations of second variable domain sequences that is encompassed by claim 57 except a second variable domain comprising the amino acid sequence of SEQ ID NOS: 9 and 10.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claim with regard to structure and function, the examples are only representative of a small group of the second variable domains. The results are not necessarily predictive of other second variable domains falling within the broadly claimed genus. Thus, it is impossible for one to extrapolate from the limited examples described herein those second variable domains that would necessarily meet the structural/functional characteristics of the rejected claim.
Mariuzza et al. (Ann. Rev. Biophys. Biophys. Chem. 1987; reference previously cited by the Examiner) reviews the structural basis of antigen-antibody recognition and teach that naturally occurring conventional antibodies comprise two polypeptides, the so-called light and heavy chains. Mariuzza et al. also teaches that the complementarity-determining regions (CDRs) of the heavy (H) and light (L) polypeptide chains of immunoglobulins determine, by their hypervariable sequences, the antigen-binding specificity of antibody molecules [page 140, first paragraph]. Therefore, changing the CDR sequence will alter the specificity of the antibody.
Wu et al. (Nature Biotechnology 2007; reference previously cited by the Examiner) teaches the design of a DVD-Ig which can be engineered from any two mAbs of distinct specificities [page 1290, right column, first paragraph]. Figure 1a (reproduced below) shows a DVD-Ig protein design with two variable domains linked in tandem in each heavy and light chain.
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One of skill in the art would have recognized the unpredictability of providing a functional DVD-Ig protein without the specification of both the first and second variable domains.
Nanna et al. (Nature Communications 2017; reference previously cited by the Examiner) teaches that a DVD is composed of variable domains of trastuzumab, h38C2 with reactive Lys, and constant domains (as shown in Figure 1a and reproduced below). Nanna et al. also teaches that to harness the Lys reactivity of h38C2 for drug attachment and enable tumor targeting, dual-variable-domains (DVDs) were engineered to combine the variable domains of h38C2 and trastuzumab. DVDs are tetravalent IgG-like molecules composed of two heavy and two light chains [page 3, right column, last paragraph bridging to page 4, left column].
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The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a genus of second variable domains that comprise a reactive residue that bind antigen.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 2, 4-8, 10, 15, 19, 23, 27, 30, 33, 34, 39, 40, 43, 46, 48, 54, 57, 58, 62, and 66.
Response to Arguments
Applicant's arguments filed April 22, 2026 have been fully considered but they are not persuasive.
Applicant asserts that amending claim 1 to more precisely specify amino acid sequences for the light and heavy chains for the dual variable domain immunoglobulin molecule (DVD-Ig) recited in claim 1 overcomes the 35 U.S.C. 112(a) written description rejection.
This argument is not found persuasive. As discussed in the 35 U.S.C. 112(a) written description rejection, the specification discloses that the dual variable domain immunoglobulin molecule comprises a first variable domain that binds to a binding target and a second variable domain that comprises a reactive residue where the linker is covalently conjugated to the reactive residue.
The specification discloses in paragraphs [00254] through [00260] that the DVD immunoglobulin comprises SEQ ID NO: 18 and 19 that binds to CD138; SEQ ID NO: 20 and SEQ ID NO: 21 that binds to BCMA; SEQ ID NO: 22 and SEQ ID NO: 23 that binds to SLAMF7; SEQ ID NO: 24 and SEQ ID NO: 25 that binds to HER2, light chain and heavy chain, respectively. Paragraph [00261] discloses that the DVD immunoglobulin comprises SEQ ID NO: 28 (a first heavy chain), SEQ ID NO: 29 (a second heavy chain), and SEQ ID NO: 30 (a light chain). The specification discloses in paragraph [00241] that an immunoglobulin molecule comprises an additional chain wherein the first heavy chain comprises a first and second variable domain, the second heavy chain comprises a first and second variable domain, and the light chain comprises a variable domain and a constant domain.
SEQ ID NOS: 9, 11, and 13 refer to a light chain and SEQ ID NOS: 10, 12, and 14 refer to a heavy chain. The specification discloses that the DVD immunoglobulin molecule includes a light chain variable domain sequence of a humanized 38C2 antibody (SEQ ID NO: 9 and 15) and a heavy chain variable domain sequence of a humanized 38C2 antibody (SEQ ID NO: 10 and 16) [00234-00235]. However, no description is provided of any other combinations of second variable domain sequences that is encompassed by claim 57 except a second variable domain comprising SEQ ID NOS: 9 and 10.
One of skill in the art would have recognized the unpredictability of providing a functional DVD-Ig protein without the specification of both the first and second variable domains. Therefore, the Examiner is maintaining the 35 U.S.C. 112(a) written description rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637
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