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 115-132 are pending in the instant application.
Claim Interpretation
Regarding 117, a “a functional variant having CDR1, HV2, HV4 and CDR2 sequences according to any thereof” is interpreted as a sequence of CDR1, HV2, HV4 and CDR2 sequence as defined in claim 115.
Objections to the Specification
A substitute specification excluding the claims is required pursuant to 37 CFR 1.125(a) because the amended specification filed 2/16/2024 did not include a marked up copy of the specification.
A substitute specification must not contain new matter. The substitute specification must be submitted with markings showing all the changes relative to the immediate prior version of the specification of record. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. An accompanying clean version (without markings) and a statement that the substitute specification contains no new matter must also be supplied. Numbering the paragraphs of the specification of record is not considered a change that must be shown.
Objections to the Claims
Claims 119 and 123 are objected to because of the following informalities: Regarding claim 119, the claim is missing the word “molecule” after “antigen-binding”. Regarding claim 119, there is a superfluous “wherein” prior to claim 123 option (c). Appropriate correction is required.
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.
Claim 127 is 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. The claim is a specific antigen binding molecule “for use” in the treatment of cancer, but it doesn’t further limit the structure of the antigen-binding molecule of claim 115. 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(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 116, 118, 120, 123, 125, 127-130, and 132 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.
Regarding claims 116, 118, 120, 123, 125, 127-130, and 132, the claims list a genus followed by the term “optionally”, “preferably”, or “such as” then describes species of the genus. It is not clear whether the recitation of the species are an optionally preferred example—and therefore not limiting—or further limitations of the scope of the claim.
The genus with optional species described are: claim 116) recitation of FW1-FW4 within an amino acid number range, optionally - selected from a group of SEQ ID NO:; claim 118) recitation of an affinity constant range, preferably - preferably 0.1 to 30 nM - even more preferably 0.1 to 10 nM; claim 120) recitation of an Fc region, optionally – Fc region species; claim 120) (a) recitation of an Fc region, further optionally – Fc heavy chain species; claim 120) (c) recitation of an Fc region substitution, further optionally – Fc mutation species; claim 123) recitation of biologically active proteins, optionally – biologically active protein species; claim 123) (a) recitation of biologically active proteins, optionally – biologically active protein species; claim 123) (d) recitation of an Fc region substitution, optionally – Fc mutation species; claim 125) recitation of a cell, preferably – an engineered T cell; claim 127) recitation of cancer, optionally – ROR1-positive cancer; claim 127) recitation of cancer, optionally – cancer type species; claim 127) recitation of blood cancers, such as – blood cancer species; claim 128) recitation of a second moiety, optionally – moiety species; claim 128) recitation of a toxin, optionally – toxin species; claim 128) recitation of anthracyclines, preferably PNU-derived anthracyclines; claim 128) recitation of amanitin derivatives, preferably alpha-amanitin derivatives; claim 128) recitation of radioisotopes, such as an alpha-emitting radionuclide, such as 227 Th or 225 Ac; claim 129) recitation of a ROR1 specific antigen binding molecule, optionally target binding molecule drug conjugate species; claim 129) recitation of linkers, optionally species of [L2]; claim 130) recitation of a ROR1 specific antigen binding molecule, optionally [Z] species; claim 132) (d) recitation of a Fc dimerization engineering type, optionally Fc dimerization engineering species; claim 132) (e) recitation of a Fc mutations, optionally Fc mutations species;
Regarding claim 120, a “functional variant” is claimed of formula (I), but it is unclear if the functional variant of the recombinant fusion protein of formula (I) is required to maintain the structure of formula (I) or if any antigen binding molecule comprising an amino acid sequence is a “functional variant”. Thus, a “functional variant” is indefinite and the meets and bounds of the claim are unclear.
Regarding claims 120 (b), 123 (e), and 132 (d), the content of the parentheses for knobs-into holes (Y-T) and knobs-into-holes (CW-CSAV) does not define or equate to the preceding terminology and thus is exemplary claim language which is unclear.
Regarding claims 120 (b), 123 (e), and 132 (d), the abbreviations for HA-TF, ZW1, EW-RVT are not defined in the claim or specification. Thus, the metes and bounds of the claim are unclear.
Claims 120, 123, and 132 contains the trademark/trade name Triomab®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe trifunctional, bispecific antibodies and, accordingly, the identification/description is indefinite.
Claim 123 recites the limitation "ROR1-specific antigen binding molecule" in line 1. There is insufficient antecedent basis for this limitation in the claim. An ROR1-specific antigen binding molecule has not yet been introduced. It is further unclear whether the ROR1-specific antigen binding molecule is an additional antigen binding molecule or is required to have a structure of formula (I).
Regarding instant claim 127, the meets and bound of the claims are indefinite. MPEP 2173.05(q) states attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness. Recitation of a use without any active, positive steps delimiting how this use is actually practiced is indefinite.
Regarding instant claim 128, the meets and bounds of the second moiety of (c) are unclear because the list is required to be selected from a group but and/or is present in two locations in the list and neither location is before the last option on the list. An ---and--- should be located after the penultimate option Pyridinobenzodiazepines.
Regarding instant claim 128, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 129, the claim recites molecular formulas -(CH2)n- and -(CH2CH2O)n- but does not describe the values for the variable n. Thus, the claim is indefinite and the metes and bounds are unclear.
Claim Rejections – 35 USC § 112(a)
Claims 115-119 and 124-132 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 115 allows for exchange of CDR1, HV2, HV4, and CDR3 that have different sequences from separate clones for recombination, but the Applicant has not tested exchange of all CDR1, HV2, HV4, and CDR3 options for the binding determinant regions. Claims 116-119 and 124-132 depend on claim 115 and also allow exchange of CDR1, HV2, HV4, and CDR3 with different sequences; and
Claim 115 claims CDR3 as SEQ ID NO:20, but this CDR3 was not tested in any VNAR clones in the disclosure. Claims 116-119 and 124-132 depend on claim 115 and also allow inclusion of SEQ ID NO:20;
Claims 124-125 claim a chimeric antigen receptor alone or wherein the receptor is within a cell that is not required to be a T or NK cell;
Claim 127 does not require the cancer cells to express ROR1 but the instant disclosure does show that cancer cells that don’t express ROR1 can be targeted by a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4.
Scope of the claimed antibodies and description in specification
The claims 115-119 and 124-132 claim a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4. The claims allow exchange of CDR1, HV2, HV4, and CDR3 binding determinants;
Claim 115 further claims CDR3 as SEQ ID NO:20 in the ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I). Claims 116-119 and 124-132 depend on claim 115 and also allow inclusion of SEQ ID NO:20; and
Claims 124- 125 claims a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 in a chimeric antigen receptor alone or wherein the receptor is within a cell that is not required to be in a T cell.
Claim 127 claims use of a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 in cancer treatment wherein the cancer is not required to express ROR1.
Summary of Species Disclosed
The disclosure taught 27 clones that include the claimed subject matter of a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4. Characterization of B1 loop library variants are shown in Table 5 of the instant specification on page 99, wherein the clones tested showed differential levels of binding in an ELISA assay.
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For example, A10CP and 1H8 differ by sequence in one amino acid in CDR1 and CDR3, but have different binding properties toward hROR1
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Further, CDR3 of SEQ ID NO:20 is not present in any of the clones tested in the disclosure. Further, multiple binding determinant changes are present in 1E2, C3CP-G4, 1H8-G4, G3CP-G4, and B1-G4. Regarding, C3CP-G4, 1H8-G4, G3CP-G4, and B1-G4, the ROR1 antibody clones comprising CDR1 SEQ ID NO:5 are only present in anti-ROR1 antibodies when the antibody further comprises HV2 SEQ ID NO:7 and HV4 SEQ ID NO:9, which include mutations not present in other clones. Thus, it is unknown if mixing of CDR1 SEQ ID NO:5, HV2 SEQ ID NO:7, and HV4 SEQ ID NO:9 would produce an effective ROR1 antibody that is secreted. Additionally, the ROR1 antibody clone 1E2 clone is the only antibody clone with CDR1 SEQ ID NO:2 and CDR3 SEQ ID NO:11, which have 3 unique substitutions. Thus, it is unknown if mixing of CDR1 SEQ ID NO:2 and CDR3 SEQ ID NO:11 would produce an effective ROR1 antibody that is secreted.
Thus, the Applicant has not tested mixture of all combination of the CDR1, HV2, HV4, and CDR3.
Alignment by Clustal Omega (https://www.ebi.ac.uk/jdispatcher/msa/clustalo) of the CDR1, HV2, HV4, and CDR3 of the 27 clones is below.
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Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. As noted above, the art generally accepted the hypervariable binding loops CDR1, HV2, HV4, and CDR3 bind to the epitope of the antigen. But the specification shows that a variation of binding is possible from a small number of changes to the binding determinant regions. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for ROR1 antigen binding molecules other than those comprising all 4 hypervariable binding loops within the individual clones tested in the ROR1 antigen binding molecule with the structure FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4.
3) When given the broadest reasonably interpretation, a population of cells that express the CAR polypeptide includes any type of cell, such as common cells from cell lines such as CHO and HeLa cell lines. The specification teaches populations of T cells. The specification fails to teach how a CAR expressed alone or in a generic cell expressing the CAR of claims 124-125 can exert effector functions which result in an anti-tumor effect. The specification provides no guidance or suggestions on how to engineer such a cell which is not a cell with effector function such as a NK cell or a T cell. One of skill in the art would be subject to undue experimentation in order to use the broadly claimed generic cells which are not a population of CAR-T cells or CAR-NK cells.
The instant specification cites that Chimeric antigen receptor T-cells targeting ROR1 have also been reported (Hudecek M et al. Clin.Cancer Res., 2013, 19, 3153-64) and describes prophetic examples of CARs based on the ROR1-specific antigen binding molecules may be generated. Furthermore, engineered T cells expressing such a CAR may also be generated, which may then be used in, for example, adoptive cell therapy (specification, page 127, example 11). No examples of a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 in a chimeric antigen receptor alone or wherein the receptor is within a cell that is not a T cell is shown.
4) Fig. 3 of the instant disclose shows that low expression of ROR1 in A427 cells does not allow for binding of the VNAR anti-ROR1 antibody clones. Cells that do not express ROR1 would not bind the VNAR anti-ROR1 antibody clones.
State of the relevant art
Structurally, VNAR domains have a classic immunoglobulin fold and superimposition of human variable heavy and light chains onto VNAR domains, revealed a structural relatedness within the core framework (Barelle C et al. (Antibodies 2015, 4, 240-258) page 244, second paragraph). Barelle further taught that at approximately 12 kDa, VNAR domains are the smallest naturally occurring independent binding domains in the vertebrate kingdom, and yet they are capable of binding to targets with high affinity and exquisite selectivity (page 246, second to last paragraph). This ability is delivered from very large repertoire diversity achieved through antigen driven maturation of primarily four hypervariable loops (CDR1, CDR3 HV2 and HV4) (page 246, second to last paragraph). This differs from the three loops seen in a conventional antibody domain (including VHH) and translates into structural features that enhance the interface between the VNAR and its target (page 246, second to last paragraph).
The primary focus for creating library diversity has been through the comprehensive mutagenesis of CDR3, as it is this loop that is believed (mimicking the natural process for naïve VNAR repertoire diversification) to play a central role in antigen recognition and binding (Barelle, page 249, first paragraph). However the HV loops can also contribute not only to increased affinity of binding through increased interface interactions but can also bind target independently (Barelle, page 249, first paragraph). The importance of HV loop binding was demonstrated in an HV2 yeast display library from an EpCAM specific VNAR and selected domains that also bound a second protein target (Barelle, page 249, first paragraph). This novel example of bi-specificity was achieved by utilizing different loops within a single VNAR binding site structure (Barelle, page 249, first paragraph).
In more traditional mammalian antibodies, at the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa H et al. (mAbs 2017, 9(5) 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph).
Regarding claims 115-119 and 124-132, mixing and matching the hypervariable binding loops CDR1, HV2, HV4, and CDR3, no structure activity relationship exists in the specification to indicate mixing and matching of the binding determinant region is possible without altering the binding to ROR1. The specification lists ROR1 antigen binding molecules with clones that have 5 separate sequences of CDR1 (SEQ ID NO:1-5), 2 sequences of HV2 (SEQ ID NO:6-7), 2 sequences of HV4 (SEQ ID NO:8-9), and 14 sequences of CDR3. A complete set of binding determinants is required to be recited to indicate binding of an epitope to an antigen.
In general, absent at least the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
3-4) The prior art has shown that T cells comprising a CAR that targets ROR1 can kill cancer cells, but there is no evidence that: i) a CAR outside the context of a cell can kill a cancer cell or: ii) a CAR in a T cell can kill cancer cells that do not express ROR1.
Benmebarek M-R et al. (Int J Mol Sci. 2019 20(6):1283 21 pages) teach that CAR T cells bind to a target cell surface antigen through a scFv recognition domain, wherein ligand recognition provides a signal through an extracellular hinge domain and a transmembrane domain to an intracellular signaling moiety comprising, for example, a CD3 ζ chain to induce T cell activation upon antigen binding. Benmebarek et al. teach that CAR-T cells utilize, at least in part, the conventional TCR signaling machinery (page 4/21, line 4) and that once a stable immunosynapse between the antigen-binding moiety and the target antigen has been formed, the induction of target cell killing by the effector functions of the cell can proceed (page 4/21, third full paragraph). Benmebarek et al. teach that to mediate cytolytic effector functions T cells use exocytosis of cytotoxic granules and the expression of membrane bound TNF ligands (page 4/21, paragraph under the heading “Perforin and Granzyme”).
Kriegsman K et al. (European Journal of Haematology, 2018 101, pp. 750-757) teach that the NK cells mediate direct tumor lysis, cytokine modulation of effector cells and the regulation of immunosuppressive cells in the tumor environment (page 751, second column, lines 9-12). Kriegsman et al teach that direct tumor cytotoxicity of antigen activated NK T cells is mediated by release of perforin, Fas ligand, granzyme B or THFα (page 751, second column, lines 12-14).
Clambrey ET et al. (Journal of Molecular Medicine, 2014, Vol. 92, pp. 735-741) teach that the TCR heterodimer comprising the alpha chain and the beta chain is incapable of transducing signal into the cell without close physical association with a complex of signal transduction proteins which are the CD3δ, CD3ε, CD3γ and the ζ chain (page 738, lines 1-66 of the 2nd paragraph under the heading “TCR specificities, signal transduction and the T cell response”). Clambrey et al. teach in order for a T cell to be fully activated TCR signaling must occur in close spatial proximity to additional signaling transduction cascades such as the costimulatory molecules of cd28 and CD28-related proteins (page 738, lines 12-17 of the 2nd paragraph under the heading “TCR specificities, signal transduction and the T cell response”). Clambrey et al. teach that activation through the TCR coupled with the integration of multiple signaling events rapidly elicits a specific T cell response that is characterized by proliferation and acquisition of effector functions including cytokine production or the ability to induce targeted cell killing (page 738-739).
Hudecek taught the receptor tyrosine kinase-like orphan receptor 1 (ROR1) was identified as a highly expressed gene in B-cell chronic lymphocytic leukemia (B-CLL), but not normal B cells, suggesting it may serve as a tumor-specific target for therapy (Hudecek M et al. (Blood 2010 116 (22): 4532–4541.), abstract). Hudecek taught ROR1 is expressed in undifferentiated embryonic stem cells, B-CLL and mantle cell lymphoma, but not in major adult tissues apart from low levels in adipose tissue and at an early stage of B-cell development (abstract). Hudecek taught a ROR1-specific chimeric antigen receptor that when expressed in T cells from healthy donors or CLL patients conferred specific recognition of primary B-CLL and mantle cell lymphoma, including rare drug effluxing chemotherapy resistant tumor cells that have been implicated in maintaining the malignancy, but not mature normal B cells (abstract). Hudecek taught the ROR1-CAR transduced T-cell clones efficiently lysed primary B-CLL and K562 cells that were stably transfected with the ROR1-gene, but not native, ROR1-negative K562 cells, demonstrating specific recognition of ROR1 (Figure 4C).
Thus, a CAR comprising a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 is required to be in a T or NK cell.
Claim Rejections – 35 USC § 102
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 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 120 and 122 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2017/0348416 (Hasler J et al.).
Regarding instant claims 120 and 122, Hasler taught an anti-TfR1 VNAR bispecific molecule wherein a VNAR is fused to a knob-into-hole Fc region that is engineered to dimerize with a second fragment of an immunoglobin Fc region (page 43, [266-267] and Figs. 12 and 16)
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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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
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.
Claims 120-123 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/122447 (Mclean et al. IDS reference), Ridgway JB et al. (Protein Eng. 1996 Jul;9(7):617-21. doi: 10.1093/protein/9.7.617.), and US 2017/0020963 (Qu X et al.).
Regarding instant claims 120-123, ‘447 taught P3A1 VNAR hlgG1 Fc fusions, wherein the sequence of PA31 is SEQ ID NO:172, wherein a drug conjugate was conjugated to a mutated serine to cysteine site, were effective (Fig 34). ‘447 taught an N-terminal VNAR-hFc sequence cysteine engineered variant for bioconjugation as SEQ ID NO:112 (Fig 10).
‘447 did not teach including a Fc knob-into-hole P3A1 VNAR hlgG1 Fc fusion, but this is obvious in view of Ridgway and Qu.
Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can insert into an opposing hole Y407T mutation (abstract).
Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2.
It would have been obvious for a person having ordinary skill in the art to take the P3A1 VNAR hlgG1 Fc fusion drug conjugate of ‘447, wherein the sequence of PA31 is ‘447 SEQ ID NO:172 and the Fc region for drug conjugation is ‘447 SEQ ID NO:112 – and: 1) combine ‘447 SEQ ID NO:172 and ‘446 SEQ ID NO:112 to produce a P3A1 VNAR hlgG1 Fc fusion that comprised a Ser to Cys mutant conjugated to a drug; 2) a) Exchange Thr 366 for Tyr on one Fc domain to engineer the Fc to dimerize with a second Fc; and b) exchange Tyr 407 for Thr on a second Fc domain to engineer the Fc to dimerize with the first Fc, to dimerize the Fc via a knob in hole approach in view of Ridgway and Qu
This is obvious because: 1) ‘447 taught P3A1 VNAR hlgG1 Fc fusion ADCs were effective; 2a) Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can insert into an opposing hole Y407T mutation; and 2b) Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2.
There is a reasonable expectation of success because: 1) ‘447 taught P3A1 VNAR hlgG1 Fc fusion ADCs were effective; 2a) Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can effectively insert into an opposing hole Y407T mutation; and 2b) Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2. Thus, the knob-into-hole engineering would be expected to be effective and successful.
This would produce a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 comprising ‘447 SEQ ID NO:172 fusion to ‘447 SEQ ID NO:112 with a drug conjugate, wherein a) one Fc domain is engineered with a Thr366Tyr mutation to dimerize with a second Fc; and b) a second Fc domain is engineered with a Tyr407Thr
to dimerize with the first Fc, via a knob-into-hole.
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The Thr366Tyr mutation is indicated in the box above and following mutation the sequence would be 100% identical to instant SEQ ID NO:148. This meets the claim limitations of claims 120-123
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).
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Claims 115-123 and 127-131 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, 9, 16-17, 21, 25-28, and 34-35 of copending Application No. 18/874,364. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claims ‘364 claim 26 a recombinant fusion protein (instant claim 119) comprising a first recombinant protein SEQ ID NO:146 (Y407T) and SEQ ID NO:277 (T366Y), which is identical to instant SEQ ID NO:146 (instant claims 120-123) and comprises a Fc region (instant claim 128) and comprises instant SEQ ID NO:50 (instant claims 115-117), the CDR1, HV2, HV4, and CDR3 of instant claim 1,
and is humanized (instant claim 118), could be used in the treatment of cancer (instant claim 127)
Regarding instant claims 126 and 128, ‘364 copending claim 34 taught a pharmaceutical composition comprising a target binding molecule drug conjugate of a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 (I) with sequences that overlap with the instantly claimed CDR1, HV2, HV4, and CDR3, and an EGFR antigen binding molecule, and a Fc engineered to dimerize with an Fc, wherein the drug conjugate is an anthracycline (instant claims 126 and 128).
Regarding instant claims 129-131, ‘364 copending claim 17 taught the target binding molecule conjugated to the structure:
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(instant claims 129-131).
‘364 taught a recombinant fusion protein dimer comprising: a first recombinant fusion protein, wherein the first recombinant fusion protein comprises a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 (I) wherein:
- CDR3 is a CDR sequence having an amino acid sequence of YPWGAGAPYNVQWY (SEQ ID NO: 23),
- CDR1 is a CDR sequence having an amino acid sequence of GANYGLAA (SEQ ID NO: 1),
- HV2 is a hypervariable sequence having an amino acid sequence of SSNQERISIS (SEQ ID NO: 6),
- HV4 is a hypervariable sequence having an amino acid sequence of NKRTM (SEQ ID NO: 8), and wherein the first antigen binding molecule is fused to a first fragment of an immunoglobulin Fc region engineered to dimerize with a second fragment of an immunoglobulin Fc region in copending claims 1-2, 5-6, 9, 16-17, 21, 25-28, and 34-35.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 120 and 122-123 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-57 of U.S. Patent No. 12,324,837 in view of Ridgway JB et al. (Protein Eng. 1996 Jul;9(7):617-21. doi: 10.1093/protein/9.7.617.), and US 2017/0020963 (Qu X et al.).
‘837 taught ROR1 specific antigen binding molecules comprising an amino acid sequence represented by the formula (I):
FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 (I)
wherein FW1 is a framework region; CDR1 is a CDR sequence of DTSYGLYS (SEQ ID NO: 1); FW2 is a framework region; HV2 is a hypervariable sequence of TTDWERMSIG (SEQ ID NO: 6); FW3a is a framework region; HV4 is a hypervariable sequence of NKGAK (SEQ ID NO: 11); FW3b is a framework region; CDR3 is a CDR sequence of REARHPWLRQWY (SEQ ID NO: 17); and FW4 is a framework region in patented claims 1-57, wherein patented claims 19-20 taught a Fc-fusion.
The claims of ‘837 did not teach including a Fc knob-into-hole Fc fusion, but this is obvious in view of Ridgway and Qu.
Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can insert into an opposing hole Y407T mutation (abstract).
Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2.
It would have been obvious for a person having ordinary skill in the art to take the ROR1 specific antigen binding molecules comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 (I) of ‘837, – and: 1) a) Exchange Thr 366 for Tyr on one Fc domain to engineer the Fc to dimerize with a second Fc; and b) exchange Tyr 407 for Thr on a second Fc domain to engineer the Fc to dimerize with the first Fc, to dimerize the Fc via a knob in hole approach in view of Ridgway and Qu
This is obvious because: 1a) Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can insert into an opposing hole Y407T mutation; and 1b) Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2.
There is a reasonable expectation of success because: 1a) Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can effectively insert into an opposing hole Y407T mutation; and 1b) Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2. Thus, the knob-into-hole engineering would be expected to be effective and successful.
This would produce a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 wherein a) one Fc domain is engineered with a Thr366Tyr mutation to dimerize with a second Fc; and b) a second Fc domain is engineered with a Tyr407Thr to dimerize with the first Fc, via a knob-into-hole. This meets the claim limitations of claims 120 and 122-123.
Claims 120 and 122-123 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 and 33-66 of copending Application No. 19/230,346 in view of Ridgway JB et al. (Protein Eng. 1996 Jul;9(7):617-21. doi: 10.1093/protein/9.7.617.), and US 2017/0020963 (Qu X et al.).
Copending ‘346 taught ROR1 specific antigen binding molecules comprising an amino acid sequence represented by the formula (I):
FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 (I)
in copending claims 1-27 and 33-66, wherein copending claims 19-20 taught a Fc-fusion.
The claims of copending ‘346 did not teach including a Fc knob-into-hole Fc fusion, but this is obvious in view of Ridgway and Qu.
Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can insert into an opposing hole Y407T mutation (abstract).
Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2.
It would have been obvious for a person having ordinary skill in the art to take the ROR1 specific antigen binding molecules comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 (I) of copending ‘346, – and: 1) a) Exchange Thr 366 for Tyr on one Fc domain to engineer the Fc to dimerize with a second Fc; and b) exchange Tyr 407 for Thr on a second Fc domain to engineer the Fc to dimerize with the first Fc, to dimerize the Fc via a knob in hole approach in view of Ridgway and Qu
This is obvious because: 1a) Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can insert into an opposing hole Y407T mutation; and 1b) Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2.
There is a reasonable expectation of success because: 1a) Ridgway taught knobs in holes engineering facilitates construction of bispecific antibodies, wherein a T366Y knob mutation can effectively insert into an opposing hole Y407T mutation; and 1b) Qu taught an Fc knob and hole conjugate #3, comprising SEQ ID NO:14 which contained a T366Y mutation paired with SEQ ID NO:27 which contains a Y407T mutation, was effective at increasing in vivo lifetime of the conjugate in Fig 1 and effectively decreasing metastasis in Fig 2. Thus, the knob-into-hole engineering would be expected to be effective and successful.
This would produce a ROR1 specific antigen binding molecule comprising an amino acid sequence represented by the formula (I): FW1-CDR1-FW2-HV2-FW3a-HV4-FW3b-CDR3-FW4 wherein a) one Fc domain is engineered with a Thr366Tyr mutation to dimerize with a second Fc; and b) a second Fc domain is engineered with a Tyr407Thr to dimerize with the first Fc, via a knob-into-hole. This meets the claim limitations of claims 120 and 122-123.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 115-132 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643