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 .
Claim Status
Claims 2-4, 7, 8, 10, 22, 24, and 25 are pending and under consideration in the instant office action.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). References to the peptide linkers disclosed on p. 32 and p. 46 of the specification are missing SEQ ID NOs.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claims 2, 3, 7, 8, and 10 are objected to because of the following informalities: the claims recite the phrase "characterized in that" or "characterized by" unnecessarily. Although it is not indefinite, the use of the word "characterized" in claims 2, 3, 7, 8, and 10 makes the language of the claim less clear and precise. The examiner suggests the following amendments:
2. A multispecific antibody, wherein the antibody comprises…
3. A fusion protein, wherein the fusion protein comprises…
7. A method of producing an antibody
8. An immunoconjugate
10. A pharmaceutical composition
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 2-4, 7, 8, 10, 22, 24, and 25 are 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 2 is indefinite for the recitation of formula I wherein the elements L5 and L6 have no clear definition. The metes and bounds of the claim are unclear if the identity of elements L5 and L6 are not known. For the purposes of expedited prosecution, L5 and L6 will be interpreted as the same as L1-L4 “independently a null or linker element”.
Claim 2 is indefinite for the recitation of “an antibody or antigenic fragment thereof that targets a target of interest”. It is unclear what an antigenic fragment would be considered to be. Does this refer to the antigen target of an antibody? A part of an antibody that induces an immune response (e.g. an immunogenic fragment of an antibody)? There is no definition of an “antigenic fragment thereof” in the specification, and if it does not refer to the antigen-binding portion of an antibody, it is unclear how a non-antigen binding portion would target a target of interest. For the purposes of expedited prosecution, the “antigenic fragment thereof that targets a target of interest” will be examined as if it refers to an “antigen-binding fragment thereof that targets a target of interest”.
Claim 2 is indefinite for the recitation of “the VL and VH regions, respectively, of an antibody targeting the same target of interest”. It is indefinite what the target of interest is the same as because there are four other antibody or antigen-binding fragments thereof that target a target of interest. It is unclear whether the target of interest is the same as each other, or the same as another one or more of the binding domains.
Claim 3 is indefinite for the recitation of “the first polypeptide of the multispecific antibody has a structure represented by Formula III from N-terminus to C-terminus, -- A3-L5-CH1-L6-Fc. However, claim 2 from which claim 3 depends requires the first polypeptide to have the formula A3-L4-B2-L5-CH1-L6-A4. The claim is unclear because the Fc domain cannot be linked at the C-terminus of L6 if the A4 antibody or antigen-binding fragment thereof is positioned there, and these are mutually exclusive domains. The indefiniteness of claim 3 is such that it cannot be further examined on the merits.
Claim 8 is indefinite the recitation of “or an enzyme” and “or a combination thereof” in the Markush group of coupling moieties recited in part b. The Markush group is recited as a closed group “consisting of” (line 4), but uses “or” before two elements, one in the middle of the Markush group. The examiner suggests amending to delete the word “or” before “an enzyme” in the list and amend to close the group with “and a combination thereof” (See MPEP 2117.I).
Claim 22 is indefinite for the recitation of the first polypeptide comprises A3-L5-CH1-L6-Fc. However, claim 2 from which claim 22 ultimately depends requires the first polypeptide to have the formula A3-L4-B2-L5-CH1-L6-A4. The claim is unclear because the Fc domain cannot be linked at the C-terminus of L6 if the A4 antibody or antigen-binding fragment thereof is positioned there, and these are mutually exclusive domains. The indefiniteness of claim 22 is such that it cannot be further examined on the merits.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3, 22, and 25 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 3, 22, and 25 are broader than what is required of claim 2 from which they depend because claim 3 recites that the multispecific comprises a first polypeptide of Formula III A3-L5-CH1-L6-Fc, whereas claim 2 requires the Formula I A3-L4-B2-L5-CH1-L6-A4, wherein A4 is an antibody or antigen-binding fragment thereof that targets a target of interest (as described in the 112b above, the instantly recited "antibody or antigenic fragment thereof" is unclear); therefore, Claim 3 does not require the A4 fragment and is thus broader than the instantly claimed. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
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 24 and 25 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: 1) cancer treatment; and 2) treatment of cancers express the target molecule of interest targeted by at least one antibody or antigen-binding domain of the multispecific antibody of claim 2, does not reasonably provide enablement for 1) cancer prevention; 2) treatment of any cancer expressing a target molecule of interest, regardless of which antigens are targeted by the binding domains of the multispecific antibody. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claims 24 and 25 are for methods of treating or preventing tumors, but the specification does not enable methods of preventing cancer.
Claims 24 and 25 are directed towards a method of treating tumors expressing target molecules of interest comprising administering the multispecific antibody of claim 2 or an immunoconjugate comprising the multispecific antibody, but the specification does not enable treatment of cancer expressing any target of interest with multispecific polypeptides comprising antigen binding domains targeting a target of interest not expressed by the cancer in the absence of a PD-1 or TIGIT binding domain wherein the binding domain blocks immunosuppression of T cell activity against a tumor. For example, inhibition of the PD-1/PD-L1 pathway may increase T cell activity against a tumor.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These
factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention.
Claims 24 and 25 are directed towards a method for treating or preventing tumors expressing target molecules of interest, comprising administering the multispecific antibody of claim 2 or an immunoconjugate comprising the multispecific antibody (claim 24), or the fusion protein of claim 3 (claim 25).
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art.
Cancer has a wide variety of causes, from environmental and/or developmental exposure to ionizing radiation and/or chemical exposure in addition to some types viral and bacterial exposure (Lichtman MA et al. The Oncologist 2017; 22(5); 542–548). Even though cancer is featured by the infinite cell proliferation, its pathogenesis is extremely complex and related to many mechanisms. In general, the hallmarks of cancer consist of ten biological capabilities during the development of cancers, namely sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, tumor-promoting inflammation, genome instability and mutation, evading immune destruction and reprogramming energy metabolism (Hanahan D et al. Cell 2011 144(5) p646-674, Figures 1 and 3). More than 100 types of cancer have been identified which are typically termed for the organs or tissues where they occur. Hanahan taught over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues (page 661, right column second to last paragraph). Hanahan taught many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (page 662, left column, first paragraph).
Clinical trials aimed at proving preventative cancer activity attributable to a specific intervention are largely infeasible, due to the impossibly large number of subjects and an equally impossible long timeframe. Although cancer is a common disease, specific types of cancer are still relatively infrequent events in an otherwise healthy population. Therefore, trials with cancer incidence as endpoints would necessarily involve several thousands of subjects followed for several decades. Such logistic difficulties have precluded cancer prevention trials with cancer incidence as an endpoint in all but a selected few malignancies for treatments such as tamoxifen and finasteride (Lee KW et al. Nature Reviews Cancer 2011 11 211-218, page 211, left column last paragraph). Lee further taught although many reports have suggested benefits and targets of phytochemicals, these reports mainly rely on cell and animal models (page 216, right column last paragraph). Lee taught that in order to apply phytochemicals as personalized cancer preventive agents, the effects of phytochemicals in humans will need to be assessed (page 216, right column last paragraph).
It is generally accepted in the art that in order for a tumor to be treating with an antibody or antigen-binding domain, a particular level of the target antigen must be expressed on the surface of the tumor being treated. For example, the fusion protein therapy targeting CD28 on T-cells via a CTLA-4 extracellular domain was shown to be rendered ineffective caused by the downregulation or loss of membrane expression of CD28 on some effector-memory T cells (de Graav, G.N., et. al., 2016. Down-regulation of surface CD28 under belatacept treatment: an escape mechanism for antigen-reactive T-cells. PloS one, 11(2), p.e0148604). Ferris et. al. (Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol. 2010 Oct 1;28(28):4390-9. doi: 10.1200/JCO.2009.27.6360. Epub 2010 Aug 9. PMID: 20697078; PMCID: PMC2954137) teach that expression and density of the targeted TA has been shown to influence the extent of monoclonal antibody-mediated lysis in vitro and that although clinical data has been conflicting, the discrepancy is likely to reflect lack of sensitivity for tumor antigen detection or immunologic variables (p. 4392). Ferris et. al. further teach: “We note that nonimmune escape from TA-targeted mAb therapy may occur, mediated by accessory signaling pathways that compensate for blockade of the pathways downstream of the targeted TA. Indeed, recent evidence from cetuximab-resistant tumor systems indicates that treatment escape may be mediated by upregulation of G-protein coupled receptors that can bypass the inhibited Erb-B receptor targeted by the mAb or expression of other HER family receptors, such as HER2 or HER3. This is corroborated by the value of elevated levels of ErbB family ligands as predictors of clinical response to trastuzumab and cetuximab.” (p. 4395 left column). Thus, the expectation is that patients with tumors that do not possess expression of the particular antigen targeted by the multispecific polypeptide would not be treated by the administration.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The specification does not show any methods of tumor treatment comprising the multispecific polypeptides (e.g. in vitro or in vivo assays showing cytotoxicity against tumor cells). There are no cancer prevention studies in the instant specification.
The specification only shows antigen binding ability of a PD-1/TIGIT/HSA trispecific (Examples 1.3-1.5). The PD-1 trispecific also blocks PD-L1 binding by PD-1 (Example 1.6). In this case, both the PD-1 and the TIGIT would be expect to be expressed on T cells rather than on the tumor cells; an anti-VEGF/PD-L1/HSA trispecific antibody (Example 2); an anti PD-L1/PD-L2/HSA (Example 3); an anti-PD-L1/4-1BB/HAS trispecific (Example 4); and an anti-PD-L1/PD-L2 bispecific Fc fusion protein (Example 5); all of the anti-PD-1 or anti-PD-L1 blocking domains show blocking of PD-1/PD-L1 which would be expected to increase immune response against a tumor (Examples 3.5, 3.6, 4.6). There are no examples of treatment of a tumor directly as described for (1), therefore there are no examples of treatment of the tumor wherein the multispecific does not have an antibody binding domain against the tumor target of interest or wherein the multispecific does not block a known T-cell checkpoint domain (e.g. PD-1, PD-L1, or TIGIT). The examiner would also like to note that several of the species of discloses multispecific antibodies do not conform to the requirements of Claim 2 (e.g. see Fig. 1A-1B, which lack either the A1 or the A3 domain in each case).
Conclusion
The Applicant does not have enablement for a method of preventing cancer by administering a multispecific polypeptide comprising Formula I and Formula II of claim 2.
The Applicant does not have enablement for a method of treating a cancer expressing any target of interest regardless of which antigen binding domains the multispecific which is administered targets and regardless of the effector mechanism of the multispecific (e.g. PD-1/PD-L1 blocking).
Dependent claims are rejected for failing to resolve the scope of enablement issue as described. The examiner suggests obviating this rejection by 1) amending the claims to delete preventing a tumor and 2) amending either the multispecific polypeptide claims (2 and 3) or the methods claims to limit the method of treatment such that the targets of interest that are bound by the polypeptides are the same targets of interest expressed by the cancer being treated.
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.
Claim(s) 2, 4, 7, 8, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2007085837 to Grosveld et. al. published 2 August 2007 (of record, cited in IDS dated 6/7/2024) as evidenced by Liu H, May K. Disulfide bond structures of IgG molecules: structural variations, chemical modifications and possible impacts to stability and biological function. MAbs. 2012 Jan-Feb;4(1):17-23. doi: 10.4161/mabs.4.1.18347. PMID: 22327427; PMCID: PMC3338938.
Claim interpretation: Claim 2 recites a “A multispecific antibody, characterized in that the antibody comprises a first polypeptide represented by Formula I from N-terminus to C-terminus and a second polypeptide represented by Formula II from N-terminus to C-terminus, A1-L1-B1-L2-CL-L3-A2 (Formula II) A3-L4-B2-L5-CH1-L6-A4 (Formula I) wherein, A1, A2, A3, and A4 are each independently an antibody or antigenic fragment thereof that targets a target of interest, and the target antigens targeted by each of Al, A2, A3, and A4 can be the same or different; L1, L2, L3, and L4 are each independently a null or linker element; B 1 and B2 are both null, or B 1 and B2 are the VL and VH regions, respectively, of an antibody targeting the same target of interest; and a disulfide bond is formed between the CL region of the second polypeptide and the CH1 region of the first polypeptide, such that the antibody has a heterodimeric form, wherein either A1 or A3 or both are VHH”. The broadest reasonable interpretation is that the minimal requirements of claim 2 are, from N to C terminus of polypeptide 1: A3-CH1-A4; and from N to C terminus of polypeptide 2: A1-CL-A2. See 112(b) rejections above regarding interpretation of undefined L5 and L6; wherein A1, A2, A3, and A4 are antibodies or antigen-binding fragments thereof, and wherein A1 or A3, or both, are VHH.
Grosveld et. al. teaches a polypeptide binding complex comprising a dimer of a first polypeptide chain and a second polypeptide chain, wherein each polypeptide comprises an amino terminal VH binding domain, a carboxy terminal VH binding domain, and a dimerization domain wherein the dimerization domain lacks CH2-CH3 functionality (claim 1 p. 32). The polypeptide binding complex can have multispecificity (Claims 6 and 7 p. 32, Abstract, p. 6 line 7, p. 18 line 25). The VH binding domains are single-chain heavy-chain only antibodies (reads on VHH, see p. 5 lines 20-31, p. 7 lines 3-19). The dimerization domain is a CH1 heavy chain domain for one polypeptide, and a light chain constant domain in the other polypeptide, which forms a stable heterodimer (p. 12 lines 2-5, p. 2 lines 24-26). Grosveld states “A dimerization domain according to the first and second aspect of the invention may be any protein, peptide fragment or consensus sequence capable of forming a homo or heterodimer protein-protein interaction, such as that seen between: CH2-CH3 region of the immunoglobulin heavy chain constant regions, the CH1 domain of an immunoglobulin heavy chain and the constant region of an immunoglobulin light chain, or the homodimerization of the 180 amino acid carboxyl terminal domain of the TATA binding protein…” (p. 16 lines 16-25). Example 1 teaches a particular embodiment wherein the CH2CH3 domain are deleted and replaced with a CH1/CL domain (p. 27). The CH1/CL dimerization domain inherently comprises a disulfide bond (Liu et. al., see Fig. 1, “Classical Disulfide Bond Structures” section ¶2). The dimerization domain is connected at the amino and carboxy terminus to the VH domains by a flexible hinge domain (reads on linkers L1, L3, L4, and L6, p. 8 lines 29-30).
Regarding claim 4, Grosveld et. al. teaches a nucleic acid encoding the first heavy chain, the second heavy chain, or both heavy chains of the invention, or vectors comprising the nucleic acids (p. 8 lines 31-32; p. 18 lines 1-9).
Regarding claim 7, Grosveld teaches a method of producing the polypeptide binding complex comprising culturing host cells transformed with vectors encoding the polypeptide of the invention (reads on host culturing host cell comprising the polynucleotides or a vector comprising the polynucleotides encoding the first and second polypeptide) (p. 18 lines 1-9); Grosveld further teaches recovering the polypeptide to provide the complete polypeptide binding complex (reads on purifying and/or isolating) (p. 24 lines 11-21). Also see p. 34 claim 18.
Regarding claim 8, Grosveld teaches a composition comprising the multispecific binding polypeptide and an effector moiety, wherein the effector moiety may be a drug or a toxin, a radionuclide, or an imaging agent (p. 14 line 29- p. 15 line 5).
Regarding claim 10, Grosveld teaches pharmaceutical compositions comprising the polypeptide and a pharmacologically appropriate carrier (p. 9 lines 10-13; p. 20 lines 18-19; p. 25 lines 4-11; p. 34 claim 21).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 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.
Claim(s) 24 is rejected under 35 U.S.C. 103 as being unpatentable over WO2007085837 to Grosveld et. al. published 2 August 2007 (of record, cited in IDS dated 6/7/2024) as evidenced by Liu H, May K. Disulfide bond structures of IgG molecules: structural variations, chemical modifications and possible impacts to stability and biological function. MAbs. 2012 Jan-Feb;4(1):17-23. doi: 10.4161/mabs.4.1.18347. PMID: 22327427; PMCID: PMC3338938 as applied to claim 2 above, and further in view of US 20170368169 to Loew et. al. published 28 December 2017.
The teachings of Grosveld et. al. in regards to claim 2 are in the 102 rejection above.
Grosveld et. al. further teaches: “The invention also provides the use of a polypeptide binding complex according to the invention in the preparation of a medicament for the prophylaxis or treatment of disease” (p. 9 lines 14-19); “The invention also provides a method of treating a patient by administering a pharmaceutical composition or a vector of the invention to the patient” (p. 9 lines 10-13); “If an amino terminal antigen-specific VH binding domain targets a cancer cell surface marker, the carboxyl terminal VH may bind an effector moiety comprising a pro-drug converting enzyme” (p. 16 lines 29-32); “Bi-specific binding proteins incorporating antibodies alone or in combination with other binding agents show promise for treatment modalities where captured human immune functions elicit a therapeutic effect, for example the elimination of pathogens […], the treatment of cancer […], and immunotherapy […]” (p. 1 line 26- p. 2 line 4).
Grosveld et. al. does not explicitly teach a method of treating comprising administering the multispecific polypeptide wherein the method is a method of treating tumors.
This deficiency is resolved by Loew et. al. Loew et. al. teaches multispecific antibodies and methods of treatment of cancer (reads on treating tumors) comprising the multispecific antibodies (Abstract). The multispecific antibodies are in the format VL-CL-(moiety A) and VH-CH1-(moiety B) (Fig. 3C), wherein the moiety A and moiety B may be a VHH domain [0434]. The multispecific or multifunctional antibodies of the invention are administered to a subject in need thereof in an amount effective to treat cancer or decrease the size of a tumor (reads on treating a tumor) ([1171]). The multispecific antibodies comprise a tumor-targeting moiety that binds to a cancer antigen [0006], for example CD123 and CD47 [0027] (reads on target of interest).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to administer the multispecific of Grosveld in a method of treating a tumor as a particular embodiment of the methods of treating cancer as implied by Grosveld and explicitly taught by Loew et. al. This would have a predictable effect because both the multispecific of Grosveld and the multispecific of Loew et. al. are customizable for the treatment of targets of interest by customizing the binding domains and comprise only a CL-CH1 dimerization domain with multiple antigen-binding domains in order to specifically target an effector moiety to a target cell as taught by Grosveld.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
EP 2658869 B1 teaches a multispecific antibody comprising single-domain antibody binding fragments dimerized by a CH1/Ck domain comprising a disulfide bond (See Figure 1)
WO2018191438 A1 teaches multispecific antibodies comprising antigen binding domain such as single domain antibodies and comprises a heterodimeric Fc domain binding a tumor associated antigen and a CD3 binding Fab (See Fig. 1, Fig. 3 bottom right panel)
WO2014198748 (of record, cited on IDS dated 6/7/2024) teaches a bispecific “bsFab” format comprising two VH domains and a CH1/Ck dimerization domain (Fig 2, top left)
WO2019134710 (of record, cited on IDS dated 6/7/2024) teaches a multispecific antibody comprising four N- and C- terminal VHH domains connected to a full-length antibody comprising CH1/CL domains and CH2/CH3 domains (Fig. 5-7)
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kathleen CunningChen whose telephone number is (703)756-1359. The examiner can normally be reached Monday - Friday 11-8:30 ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Janet Epps-Smith can be reached at (571) 272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/ANAND U DESAI/Primary Examiner, Art Unit 1656