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 1-2, 4-5, 7-12, 14-16 and 18-24 are pending in the application and are under examination.
Information Disclosure Statement
The information disclosure statements have been considered.
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 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, 7-9, 11-12, 14-16 and 18-24 are rejected under 35 U.S.C. 103 as being unpatentable over Santich et al (WO 2020/113164 A1, IDS), Sanders et al (WO 2004/050708 A2, IDS) and Cheung et al (WO 2016/014942 A1, IDS).
With respect to claims 1 and 4, Santich discloses in Figure 1 multispecific antibodies having the structures:
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Santich et al discloses in the second structure presented here a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain (a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain; paragraph [0006]), wherein the first and second polypeptide chains are covalently bonded to one another (wherein the first and second polypeptide chains are covalently bonded to one another; paragraph [0006]), the second and third polypeptide chains are covalently bonded to one another (the second and third polypeptide chains are covalently bonded to one another; paragraph [0006]), and the third and fourth polypeptide chain (and the third and fourth polypeptide chain; paragraph [0006]), and wherein: (a) the first polypeptide chain comprises in the N-terminal to C-terminal direction: (i) a light chain variable domain of a first immunoglobulin (VL-1) that is capable of specifically binding to a first epitope (and wherein: (a) the first polypeptide chain comprises in the N-terminal to C-terminal direction: a light chain variable domain of a first immunoglobulin that is capable of specifically binding to a first epitope; paragraph [0006]); (ii) a light chain constant domain of the first immunoglobulin (CL-1) (a light chain constant domain of the first immunoglobulin; paragraph [0006]); (iii) a flexible peptide linker
comprising the amino acid sequence (GGGGS)3 (a flexible peptide linker comprising the amino acid sequence (GGGGS)3; paragraph [0006]); and (iv) a light chain variable domain of a second immunoglobulin (VL-2) that is linked to a complementary heavy chain variable domain of the second immunoglobulin (VH-2), or a heavy chain variable domain of a second immunoglobulin (VH-2) that is linked to a complementary light chain variable domain of the second immunoglobulin (VL-2) (a light chain variable domain of a second immunoglobulin (VL-2) that is linked to a complementary heavy chain variable domain of the second immunoglobulin (VH-2), or a heavy chain variable domain of a second immunoglobulin (VH-2) that is linked to a complementary light chain variable domain of the second
immunoglobulin (VL-2); paragraph [0006]), wherein VL-2 and VH-2 are capable of specifically binding to a second epitope (wherein VL-2 and VH-2 are capable of specifically binding to a second epitope; paragraph [0006]), and are linked together via a flexible peptide linker comprising the amino acid sequence (GGGGS)6 to form a single-chain variable fragment (and are linked together via a flexible peptide linker comprising the amino acid sequence (GGGGS)6 to form a single-chain variable fragment; paragraph [0006]); (b) the second polypeptide chain comprises in the N-terminal to C-terminal direction: (i) a heavy chain variable domain of the first immunoglobulin (VH-1) that is capable of specifically binding to the first epitope (the second polypeptide chain comprises in the N-terminal to C-terminal direction: (i) a heavy chain variable domain of the first immunoglobulin (VH-1) that is capable of specifically binding to the first epitope; paragraph [0006]).
Santich et al discloses in the first structure presented here a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain (a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain; paragraph [0008]), wherein the first and second polypeptide chains are covalently bonded to one another (wherein the first and second polypeptide chains are covalently bonded to one another; paragraph [0008]), the second and third polypeptide chains are covalently bonded to one another (the second and third polypeptide chains are covalently bonded to one another; paragraph [0008]), and the third and fourth polypeptide chain (and the third and fourth polypeptide chain; paragraph [0008]), and wherein: (a) the first polypeptide chain comprises in the N-terminal to C-terminal direction: (i) a light chain variable domain of a first immunoglobulin (VL-1) that is capable of specifically binding to a first epitope (and wherein: (a) the first polypeptide chain comprises in the N-terminal to C-terminal direction: a light chain variable domain of a first immunoglobulin that is capable of specifically binding to a first epitope; paragraph [0008]); (ii) a light chain constant domain of the first immunoglobulin (CL-1) (a light chain constant domain of the first immunoglobulin; paragraph [0008]); (iii) a flexible peptide linker comprising the amino acid sequence (GGGGS)3 (a flexible peptide linker comprising the amino acid sequence (GGGGS)3; paragraph [0008]); and (iv) a light chain variable domain of a second immunoglobulin (VL-2) that is linked to a complementary heavy chain variable domain of the second immunoglobulin (VH-2), or a heavy chain variable domain of a second immunoglobulin (VH-2) that is linked to a complementary light chain variable domain of the second immunoglobulin (VL-2) (a light chain variable domain of a second immunoglobulin (VL-2) that is linked to a complementary heavy chain variable domain of the second immunoglobulin (VH-2), or a heavy chain variable domain of a second immunoglobulin (VH-2) that is linked to a complementary light chain variable domain of the second immunoglobulin (VL-2); paragraph [0008]), wherein VL-2 and VH-2 are capable of specifically binding to a second epitope (wherein VL-2 and VH-2 are capable of specifically binding to a second epitope; paragraph [0008]), and are linked together via a flexible peptide linker comprising the amino acid sequence (GGGGS)6 to form a single-chain variable fragment (and are linked together via a flexible peptide linker comprising the amino acid sequence (GGGGS)6 to form a single-chain variable fragment; paragraph [0008]); (b) the second polypeptide chain comprises in the N-terminal to C-terminal direction: (i) a heavy chain variable domain of the first immunoglobulin (VH-1) that is capable of specifically binding to the first epitope (the second polypeptide chain comprises in the N-terminal to C-terminal direction: (i) a heavy chain variable domain of the first immunoglobulin (VH-1) that is capable of specifically binding to the first epitope; paragraph [0008]); (ii) a first CH1 domain of the first immunoglobulin (CH1-1) (a first CH1 domain of the first immunoglobulin; paragraph [0008]); and (iii) a first heterodimerization domain of the first immunoglobulin, wherein the first heterodimerization domain is incapable of forming a stable homodimer with another first heterodimerization domain (a first heterodimerization domain of the first immunoglobulin, wherein the first heterodimerization domain is incapable of forming a stable homodimer with another first heterodimerization domain; paragraph [0008]); (c) the third polypeptide chain comprises in the N-terminal to C-terminal direction: (i) a heavy chain variable domain of a third
immunoglobulin (VH-3) that is capable of specifically binding to a third epitope (the third polypeptide chain comprises in the N-terminal to C-terminal direction: a heavy chain variable domain of a third immunoglobulin that is capable of specifically binding to a third epitope; paragraph [0008]); (ii) a second CH1 domain of the third immunoglobulin (CH1-3) (a second CH1 domain of the third immunoglobulin;
paragraph [0008]); and (iii) a second heterodimerization domain of the third immunoglobulin, wherein the second heterodimerization domain comprises an amino acid sequence or a nucleic acid sequence that is distinct from the first heterodimerization domain of the first immunoglobulin (a second heterodimerization domain of the third immunoglobulin, wherein the second heterodimerization domain comprises an amino acid sequence or a nucleic acid sequence that is distinct from the first heterodimerization domain of the first immunoglobulin; paragraph [0008]), wherein the second heterodimerization domain is incapable of forming a stable homodimer with another second heterodimerization domain (wherein the second heterodimerization domain is incapable of forming a stable homodimer with another second heterodimerization domain; paragraph [0008]), and wherein the second heterodimerization domain of the third immunoglobulin is configured to form a heterodimer with the first heterodimerization domain of the first immunoglobulin (wherein the second heterodimerization domain of the third immunoglobulin is configured to form a heterodimer with the first heterodimerization domain of the first immunoglobulin; paragraph [0008]); (d) the fourth polypeptide chain comprises in the N-terminal to C-terminal direction: (i) a light
chain variable domain of the third immunoglobulin (VL-3) that is capable of specifically binding to the third epitope (the fourth polypeptide chain comprises in the N-lerminal to C-terminal direction: a light chain variable domain of the third immunoglobulin that is capable of specifically binding to the third epitope; paragraph [0008]); (ii) a light chain constant domain of the third immunoglobulin (CL-3) (a light
chain constant domain of the third immunoglobulin; paragraph [0008]); (iii) a flexible peptide linker comprising the amino acid sequence (GGGGS)3 (a flexible peptide linker comprising the amino acid sequence (GGGGS)3; paragraph [0008]); and (iv) a light chain variable domain of a fourth immunoglobulin (VL-4) that is linked to a complementary heavy chain variable domain of the fourth immunoglobulin (VH-4), or a heavy chain variable domain of a fourth immunoglobulin (VH-4) that is linked to a complementary light chain variable domain of the fourth immunoglobulin (VL-4) (a light chain variable domain of a fourth immunoglobulin (VL-4) that is linked to a complementary heavy chain variable domain of the fourth immunoglobulin (VH-4 ), or a heavy chain variable domain of a fourth immunoglobulin (VH-4) that is linked to a complementary light chain variable domain of the fourth immunoglobulin (VL-4); paragraph [0008]), wherein VL-4 and VH-4 are capable of specifically binding to the fourth epitope (wherein VL-4 and VH-4 are capable of specifically binding to the fourth epitope;
paragraph [0008]), and are linked together via a flexible peptide linker comprising the amino acid sequence (GGGGS)6 to form a single-chain variable fragment (and are linked together via a flexible peptide linker comprising the amino acid sequence (GGGGS)6 to form a single-chain variable fragment; paragraph [0008]).
Santich et al discloses that the multi-specific antibodies can target antigens, such as cell surface antigens on tumor cells (paragraph [00121]) and other antigens including CD3 (paragraph [00120]). Santich et al discloses that the multi-specific antibodies can treat diseases by administering the multi-specific antibodies (paragraph [00280]).
Santich et al does not disclose a TSHR antibody wherein the heavy chain variable domain of the TSHR antibody comprises SEQ ID NO: 57 and wherein the light chain variable domain of TSHR antibody comprises SEQ ID NO: 58 or a CD3 antibody wherein the heavy chain variable domain of the CD3 antibody comprises SEQ ID NO: 61 and wherein the light chain variable domain of the CD3 antibody comprises SEQ ID NO: 63.
Sanders et al discloses a TSHR antibody wherein the heavy chain variable domain of the TSHR antibody comprises SEQ ID NO: 57 and wherein the light chain variable domain of TSHR antibody comprises SEQ ID NO: 58 (SEQ ID NO: 57 of the instant PCT application is 100% identical to SEQ ID NO: 1 of the reference; page 9, fourth paragraph and SEQ ID NO: 58 of the instant PCT application is 100%
identical to SEQ ID NO: 6 of the reference; page 9, fifth paragraph). Sanders et al discloses using the antibody in treating diseases associated with the TSH receptor such as autoimmune diseases or cancers expressing TSHR (see claims and pages 48-49). Sanders et al discloses in Graves disease TSHR antibodies mimic the action of TSH which stimulates the thyroid to produce high level of thyroid hormones and a TSH receptor blocking antibody would be valuable for when the TSH receptor requires inactivation (see pages 1 and 49-50).
Cheung et al discloses a CD3 antibody wherein the heavy chain variable domain of the CD3 antibody comprises SEQ ID NO: 61 and wherein the light chain variable domain of the CD3 antibody comprises SEQ ID NO: 63 (SEQ ID NO: 61 of the instant PCT application is 100% identical to SEQ ID NO: 64 of the reference; paragraph [0007]) and SEQ ID NO: 63 of the instant PCT application is 100% identical to SEQ ID NO: 65 of the reference; paragraph [0007]). Cheung et al discloses the CD3 antibody can be included in a multispecific antibody to bind T cells which allow T cell cytotoxicity to be redirected to the targeted antigen (the antigen bound by the different specificity, often on a tumor cell. Cheung et al discloses the other specificity binding HER2 to treat HER2 expressing cancers (see page 61). Cheung et al discloses that a HER2 antibody wherein the heavy chain variable domain of the HER2 antibody comprises SEQ ID NO:56 and wherein the light chain variable domain of HER2 antibody comprises SEQ ID NO: 54 (SEQ ID NO: 56 of the instant PCT application is 100% identical to the heavy chain variable region of SEQ ID NO: 27 of the reference and SEQ ID NO: 54 of the instant PCT application is 100% identical to the light chain variable region of SEQ ID NO: 34 of the reference; see pages 34 and 39). Cheung et al discloses arming T cells ex vivo with multispecific antibodies that bind CD3 and HER2 (see pages 56-59 and 104).
Accordingly, it would have been prima facie obvious to a person of ordinary skill in the art, at the time of the invention, to have modified the antibody, as previously disclosed by Santich et al, with the heavy chain and light chain sequences of the TSHR antibody of Sanders and with the heavy chain and light chain sequences of the CD3 antibody of Cheung et al, to provide the benefit of targeting TSH receptor and activating T cell cytotoxicity which can be used to treat thyroid diseases such as thyroid cancer and Graves’ disease as instantly claimed. Then with respect to claim 11 which recites decreasing bone remodeling, in treating Graves’ disease this method necessarily also occurs as modulating thyroid hormone levels in treating Graves’ disease also would decrease bond remodeling as Graves’ disease causes an overactive thyroid which speeds up bone-remodeling. Then in cancers expressing TSHR and HER2, it would have been obvious to also administer a multi-specific antibody targeting HER2 as this treatment would have the advantage of targeting multiple antigens on the cancer to better treat the cancer. Furthermore, arming T cells ex vivo with said TSHR/CD3 bispecific antibody and other T cells with the HER2/CD3 bispecific antibody and then administering such T cells would have been obvious because the prior art recognized that the bispecific antibodies can activate T cells such that arming T cells with bispecific antibodies as disclosed by Cheung et al would have the advantage of increasing the number of activated T cells in the patient to better treat the patient. Such methods also meet the limitations of claims 19-21 because T cells comprise the cells of claim 19 and the cells include those that are freshly harvested or cryopreserved from the subject or a third-party donor. With respect to claims 14 and 24, as the prior art discloses treating THSR positive cancers, such cancers also necessarily include cancers that are resistant to other therapies as claimed.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, absent a showing otherwise.
Conclusion
No claims are allowed. Claims 2, 5 and 10 are objected to as being dependent upon a rejected base claim.
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Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
August 21, 2026
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