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 .
Applicant’s amendment, filed on 3/03/2023, is acknowledged.
Claims 3, 4, 6, 8, 9, 12, 14-22, 24, 26, 27, 32-41, and 59-63 are cancelled
Claims 1, 2, 5, 7, 10, 11, 13, 23, 25, 28-31, 42-58 are currently pending.
Claims 1, 2, and 58 are independent claims.
Election/Restrictions
Applicants’ election of Group I, claims 1, 5, 7, 10, 11, 13, 23, 25, 28-31, and 42-57, directed to a method of treatment comprising administration of a first and second MBM; and the Species of: i) a first MBM with an anti-CD2 ABM1 with CDRH1-3 and CDRL1-3 of SEQ ID NO: 1327, 1325, 1326, 1334, 1335, and 1336, respectively, an anti-CLL-1 ABM2 with CDRH1-3 and CDRL1-3 of SEQ ID NO: 8, 45, 10, 5, 6, and 7 of US20160368994, respectively, and no ABM3, and a second MBM with an anti-CD3 ABM4 with CDRH1-3 and CDRL1-3 of SEQ ID NO: 194, 214, 238, 195, 215, and 239, respectively, and an anti-CLL-1 ABM5 with CDRH1-3 and CDRL1-3 of SEQ ID NO: 8, 45, 10, 5, 6, and 7, respectively, and no ABM6; and ii) acute myeloid leukemia (AML), filed on 11/25/2025, is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Note that the elected species of first and second MBM are not claimed and will not be examined.
Claims 2, 7, 10, 23, 25, 28-31, 46-51, and 54-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or Species.
Claims 1, 5, 11, 13, 42-45, 52, and 53 are under examination.
Priority
Applicant’s claim for the benefit of a prior-filed U.S. provisional application Nos. 63/000,693, filed March 27, 2020, and 63/111,852, filed November 10, 2020, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 3/03/2023 and 11/25/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in their entireties.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. For example, ¶[0434] and [0441] contain browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5, 11, 13, 42-45, 52, and 53 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Breadth of claims and nature of invention:
Claim 1 recites:
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Claim 1 encompasses a method of treating a subject with “a proliferative disease or an autoimmune disorder”, which includes any and all proliferative diseases and autoimmune disorders, comprising administration of a broad genus of first multispecific binding molecules comprising an antigen binding module 1 with no recited structure and the function of “binds specifically to human CD2” and an ABM2 with no recited structure and the function of “binds specifically to a human tumor-associated antigen”; and a broad genus of second multispecific binding molecules comprising an ABM4 with no recited structure and the function of “binds specifically to a component of a human TCR” and an ABM5 with no recited structure and the function of “binds specifically to a human tumor-associated antigen”. As it is currently written, the tumor associated antigen that the ABM2 and ABM5 binds to can be any tumor associated antigen.
Claim 5 encompasses the method of claim 1, wherein the ABM4 has no recited structure and the function of “binds specifically to a component of a TCR complex”.
Claim 11 encompasses the method of claim 1, wherein the ABM2 and ABM5 have no recited structure and the additional function of “binds specifically to the same TAA”.
Claim 13 encompasses the method of claim 11, wherein the ABM2 and ABM5 have no recited structure and the function of “binds specifically to CLL-1”.
Claims 42-45, 52, and 53 encompass the method of claim 1, wherein the proliferative disease or autoimmune disorder is a proliferative disease (claim 42), cancer (claim 43), a hematologic proliferative disease (claim 44), a leukemia (claims 45 and 52), or AML (claim 53).
As they are currently written, the claims encompass broad methods of treating any and all proliferative diseases or autoimmune disorders (claims 1, 5, 11, and 13), any and all proliferative diseases (claim 42), any and all cancers (claim 43), any and all hematologic malignancies (claim 44), any and all leukemias (claims 45 and 52), or AML (claim 53), comprising administration of:
A broad genus of first MBMs comprising an ABM1 with no recited structure (i.e., amino acid sequence, especially in the CDR regions crucial for antigen binding) and the function of “binds specifically to CD2”, and a ABM2 with no recited structure and the function of “binds specifically to a tumor antigen” (claims 1, 5, 11, 42-25, 52, and 53), or “binds specifically to CLL-1” (claim 13); and
A broad genus of second MBMs comprising an ABM4 with no recited structure and the function of “binds specifically to a TCR complex or a secondary T-cell signaling molecule” (claims 1, 11, 13 42-45, 52, and 53), or “binds specifically to a component of a TCR complex” (claim 5), and a ABM5 with no recited structure and the function of “binds specifically to a tumor antigen” (claims 1, 5, 11, 42-25, 52, and 53), or “binds specifically to CLL-1” (claim 13).
These broad genera of first and second MBMs with the recited functions in the claims include millions to billions of different MBM structures with two ABMs each, with each ABM structure defined by their amino acid sequences especially in the 6 CDR regions crucial for binding (when the ABM is an antibody or antigen binding fragment thereof), with the functions recited in the claims.
The specification discloses specific ABM structures that specifically bind to a variety of antigens that can be incorporated into either a first and second MBM, including CD2 binders (Table 11), BCMA binders (Tables 14 and 15), CD19 binders (Tables 16 and 17), CD20 binders (Table 18), CD22 binders (Table 19), mesothelin binders (Table 20), CD3 binders (Table 22), and TCR-α/β binders (Table 23). Notably, all examples of the structures are antibody (i.e., immunoglobulin) structures that bind to one specific antigen, except for CD2 binders, which also comprise an engineered fragment of CD58 that specifically binds to CD2. The instant specification additionally references antibody structures that bind to different antigens that have been taught in other references (Tables 13 and 24).
Furthermore, the specification discloses MBM structures that comprise: i) an anti-CD3 antibody and an anti-CD22 antibody, ii) an anti-CD2 antibody and an anti-CD22 antibody, iii) an anti-CD2 antibody and an anti-CD20 antibody (Example 3, Table 28), iv) anti-mesothelin/anti-CD3 MBMs, and v) anti-mesothelin/anti-CD2 MBMs (Example 4, Table 29).
Amount of direction and existence of working examples:
The specification discloses two exemplary antibody structures that specifically bind to CD2, (Table 11), 40 exemplary antibody structures that specifically bind to BCMA (Tables 14 and 15), 16 exemplary antibody structures that specifically bind to CD19 (Tables 16 and 17), one exemplary antibody structure that specifically binds to CD20 (Table 18), three exemplary antibody structures that specifically bind to CD22 (Table 19), two exemplary antibody structures that specifically bind to mesothelin (Table 20), 30 exemplary antibody structures that specifically bind to CD3 (Table 22), and one exemplary antibody structure that specifically binds to TCR-α/β (Table 23).
The instant specification additionally discloses working examples of MBMs comprising an anti-CD3 ABM and an anti-BCMA ABM (Example 1), two working examples of anti-CD3/anti-CD22 MBMs, six working examples of anti-CD2/anti-CD22 MBMs, and two working examples of anti-CD2/anti-CD20 MBMs (Tables 28 and 30), as well as two working examples of anti-CD3/anti-MSLN MBMs and four working examples of anti-CD2/anti-MSLN MBMs (Table 29)
The instant specification further discloses one working example of a method of eliminating tumor cells in vitro (Example 7). A combination of a species of an anti-CD2xCD20 MBM and an anti-CD3xCD19 MBM was used to engage T-cells to target and eliminate Karpas 422 cells in a co-culture of Karpass422 and T-cells (Example 8, Figure 5).
Level of predictability, state of prior art, and quantity of experimentation needed:
Regarding the broad genera of first MBMs comprising an ABM1 with no recited structure (i.e., amino acid sequence, especially in the CDR regions crucial for antigen binding when the structure is an antibody or antigen binding fragment thereof) and the function of “binds specifically to CD2”, and a ABM2 with no recited structure and the function of “binds specifically to a tumor antigen” (claims 1, 5, 11, 42-25, 52, and 53), or “binds specifically to CLL-1” (claim 13); and the broad genera of MBMs comprising an ABM4 with no recited structure and the function of “binds specifically to a TCR complex or a secondary T-cell signaling molecule” (claims 1, 11, 13 42-45, 52, and 53), or “binds specifically to a component of a TCR complex” (claim 5), and a ABM5 with no recited structure and the function of “binds specifically to a tumor antigen” (claims 1, 5, 11, 42-25, 52, and 53), or “binds specifically to CLL-1” (claim 13):
The claims are directed to broad genera of first and second MBMs comprising AMBs with no recited structure and the functions recited in the claims. These genera each include millions to billions of different structures, including antibodies and non-antibody structures with widely varying amino acid sequences and length (including, if the MBM comprises ABMs that are antibody structures, in the CDR regions that are critical for antigen binding).
However, the specification did not give the skilled in the art enough information to choose candidate antigen binding structures from the vast number of options of millions of candidates, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses multiple different examples of MBM structures with the functions recited in the claims (Tables 28-30), and different examples of ABM structures that can be incorporated into MBMs (Tables 11, 14-20, 22, and 23). Each of these MBM or ABM structures have defined amino acid sequences that determine the specific binding to an antigen. Apart from listing exemplary structures that have the functions recited in the claims, the instant specification does not disclose any guidance on which amino acid sequences (i.e., structures) would predictably give rise to MBMs with the functions recited in the claims.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
In the instant case, the claims are directed to a broad classes of MBM comprising ABMs with no recited structure and the functions of “specifically binds to CD2”, “specifically binds to CD3”, “specifically binds to a human tumor-associated antigen”, (claims 1, 42-45, 52, and 53), “specifically binds to a component of a TCR complex” (claim 5), or “specifically binds to CLL-1” (claim 13).
The instant claims are directed to a class of MBM structures, which include antibodies, that include “a ‘vast’ number” of additional structures (i.e., amino acid sequences of all of the CDR regions that are necessary for antigen binding in the case of antibodies) in which the instant specification fails to describe. It would be necessary to first generate and then screen each candidate MBM to determine whether it met the functional limitations recited in the claims. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant specification does not disclose any common structural feature delineating which antibody variants would have the functions of “specifically binds to CD2”, “specifically binds to a TCR or a secondary T-cell signaling molecule”, “specifically binds to a human tumor-associated antigen”, (claims 1, 42-45, 52, and 53), “specifically binds to a component of a TCR complex” (claim 5), or “specifically binds to CLL-1” (claim 13), or how to distinguish MBMs with these functions form those without. The only structure-function relationship guidance the specification provides is to disclose individual structures with the claimed functions.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antibody structures they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
Applicant is relying upon certain biological activities such as MBM structures that specifically bind to two different antigens, such as CD2 and CLL-1, a limited number of species with defined structures (e.g. amino acid sequences) to support an entire genus of diverse and structurally unrelated MBMs. Yet the instant specification does not provide sufficient guidance and directions as to the structural features of the MBMs and the correlation between the structure and the desired binding functions.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
Additionally, in its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be "materially indistinguishable from those in Amgen." Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers "millions of potential candidate antibodies" (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, "the '590 patent's roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose." (Id.) Missing from the specification, according to the Federal Circuit, was "'a quality common to every functional embodiment' ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions" (id.; quoting Amgen Inc. v. Sanofi., 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta's argument that its disclosed hybridoma-and screening process "predictably and reliably generates new claimed antibodies every time it is performed" (id.), because "it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions." (Id.).
Regarding the broadly claimed methods of treating any and all proliferative diseases and autoimmune diseases (claims 1, 5, 11, 13), any and all proliferative diseases (claim 42), any and all cancers (claim 43), any and all hematologic malignancies (claim 44), any and all leukemias (claims 45 and 52), or AML (claim 53) with the broadly claimed classes of MBMs recited in the claims,
The instant specification discloses one method of eliminating Karpas422 cells with a specific anti-CD2xCD20 MBM structure and a specific anti-CD3xCD19 MBM (structures both listed in instant Table 30), which is disclosed in Example 3. The combination therapy effectively induced T-cell engagement to induce tumor cell death (Figure 5).
Dyer et al. (Blood. 1990 Feb 1;75(3):709-14. PMID: 2297573) teaches that the Karpas 422 cell line is a B-cell non-Hodgkin’s lymphoma cell line (Abstract) that expresses both CD20 and CD19 (Table 1). Thus, the disclosed MBM combination was able to induce killing by engaging T-cells through two bispecific antibodies, one binding to CD20 on the Karpas 422 cells and CD2 on T-cells, and another binding to CD19 on the Karpas 422 cells and CD3 on T-cells.
However, neither the instant specification nor the prior art provides sufficient guidance to allow one with ordinary skill in the art to use methods of treating any and all proliferative diseases and autoimmune diseases with a combination of a broad genus of anti-CD2/anti-tumor associated antigen MBMs and a broad genus of anti-TCR complex or secondary T-cell signaling complex/anti-TAA MBMs (claims 1, 5, 11) or when both TAAs are CLL-1 (claim 13), or methods of treating any and all proliferative diseases (claim 42), any and all cancers (claim 43), any and all hematologic malignancies (claim 44), any and all leukemias (claims 45 and 52), or AML (claim 53) with a combination of a broad genus of anti-CD2/anti-tumor associated antigen MBMs and a broad genus of anti-TCR complex or secondary T-cell signaling complex/anti-TAA MBMs.
Undue experimentation is required by one with ordinary skill in the art to use the recited methods of treating any and all proliferative diseases and autoimmune diseases (claims 1, 5, 11, 13), any and all proliferative diseases (claim 42), any and all cancers (claim 43), any and all hematologic malignancies (claim 44), any and all leukemias (claims 45 and 52), or AML (claim 53) with the broad genre of first and second MBMs with no recited structure recited in the claims.
The specification does not reasonably provide enablement to make and use the invention of instant claims 1, 5, 11, 13, 42-45, 52, and 53.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
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.
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.
Claims 1, 5, 11, 42, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Kodama et al. (Immunol Lett. 2002 Apr 22;81(2):99-106. doi: 10.1016/s0165-2478(01)00343-1).
Instant claim 1 recites:
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In summary, instant claim 1 recites a method of treating a subject with either a proliferative disease (i.e., cancer) or an autoimmune disease, comprising administration of two MBMs, wherein the first MBM is an anti-CD2xTAA bispecific and the second MBM is an anti-TCRxTAA bispecific or an anti-secondary T-cell signaling moleculexTAA bispecific.
Kodama et al. teaches a method of treating bile-duct carcinoma cells with a combination of an anti-MUC1 (i.e., a tumor-associated antigen) x anti-CD3 bispecific antibody and an anti-MUC1 x anti-CD2 bispecific antibody (Abstract): “…we previously constructed two kinds of bispecific antibodies (bsAbs), anti-MUC1×anti-CD3 (M×3) and anti-MUC1×anti-CD28 (M×28), which activate T cells and form bridges between them and MUC1-expressing tumor cells…we developed another bsAb, anti-MUC1×anti-CD2 (M×2), in order to examine if this would show synergism with the two previously described bsAbs…”
Kodama et al. additionally teaches sensitizing T-cells in vitro with a combination of the antibodies, followed by injection of the sensitized T-cells into mice bearing bile-duct carcinoma xenografts, leading to significant reduction in tumor growth (Section 2.9 and Figure 6). Kodama further teaches (final ¶ of Section 3): “[b]y injecting triple bsAbs directly into patients, enhancement of local antitumor activity might be expected.” Thus, Kodama et al. provides motivation to use the bispecific antibody combination in a method of treating cancer such as bile duct carcinoma.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant invention, to have modified the teachings of Kodama et al. to make and use a method of treating bile-duct carcinoma (i.e., a cancer or a proliferative disease, the limitations of instant claims 1, 42, and 43) comprising administration of an anti-MUC1xanti-CD3 bispecific and an anti-MUC1xanti-CD2 bispecific, as Kodama et al. teaches these bispecific antibody structures and methods of sensitizing T-cells with these bispecific antibodies, and Kodama et al. further provides motivation to use these antibodies in a combination therapy to treat bile-duct carcinoma to enhance local antitumor activity.
Claim 5 is included because CD3 is part of the TCR complex, and claim 11 is included because both bispecifics bind the MUC-1 tumor-associated antigen.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 44, 45, 52, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Kodama et al. (supra), as applied to claims 1, 5, 11, 42, and 43 above, and further in view of Stroopinsky et al. (Cancer Res. 2013 Sep 1;73(17):5569-79. doi: 10.1158/0008-5472.CAN-13-0677. Epub 2013 Jul 18).
The teachings of Kodama et al. have been discussed supra. Kodama et al. does not teach MUC1 expression in AML cells, or methods of treating AML in a patient comprising administration of an anti-Muc1xCD3 MBM and an anti-Muc1xCD2 MBM (i.e., the limitations of instant claims 44, 45, 52, and 53).
Stroopinsky et al., in the same field of endeavor, teaches that Muc1 is highly expressed on AML lineage cells (Abstract and Figure 1): “[h]ere, we report that MUC1 is highly expressed on AML CD34+/lineage−/CD38− cells as compared to their normal stem cell counterparts. MUC1 expression was not restricted to AML CD34+ populations as similar results were obtained with leukemic cells from patients with CD34− disease”. Stroopinsky et al. teaches that Muc1 expression drives AML expansion (Abstract and Figure 3): “[e]ngraftment of AML stem cell populations that highly express MUC1 (MUC1high) led to development of leukemia in NSG immunodeficient mice. In contrast, MUC1low cell populations established normal hematopoiesis in the NSG model.”
Stroopinsky et al. further teaches that inhibition of Muc1 with the Muc1 inhibitor GO-203 in AML cells reduces tumor growth in vivo (Pg 7, ¶1 and Figure 6): “…treatment with GO-203 was associated with a marked decrease in leukemic cell involvement (Fig. 6E, right) that was significantly different from that found in the bone marrows of the PBS treated mice (Fig. 6F)”.
Stroopinsky et al. additionally teaches (Discussion): “…GO-203 was effective in treating leukemia that was established in NSG mice inoculated with the AML CD34+/lineage−/MUC1high population…[i]n summary, our findings provide evidence that MUC1 is highly expressed on AML stem cells as compared to their normal counterparts and that MUC1 is a selective target for the treatment of AML…”
Stroopinsky et al. teaches: 1) Muc1 is expressed on AML cells and can drive the expansion of AML cells; and 2) Muc1 is a target for anti-cancer therapies targeting Muc1, as inhibition of Muc1 reduced cancer cell progression, establishing Muc1 as a selective target to treat AML in patients.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have modified the teachings of Kodama et al. in view of Stroopinsky et al. to use the method of treatment comprising administration of a Muc1xCD3 bispecific and a Muc1xCD2 bispecific to treat AML with a reasonable expectation of success, as Kodama et al. teaches bispecific antibody combination therapies that one with ordinary skill in the art would be able to apply to treat AML, given the teachings of Stroopinsky et al. that Muc1 is a selective target to treat AML in patients. One would have motivated to make this change to apply the combination cancer therapy taught by Kodama et al. to AML, which expresses Muc1 as a selective target, such as AML (as suggested by Stroopinsky et al.).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 5, 11, 42-45, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 12,221,481 (herein Pat ‘481) in view of Wu et al. (J Hematol Oncol. 2015 Sep 4;8:104. doi: 10.1186/s13045-015-0195-4). Although the claims at issue are not identical, they are not patentably distinct from each other.
Pat ‘481 claims a trispecific binding molecule (i.e. “a first MBM”) comprising an ABM that specifically binds to CD2 (i.e. “ABM1”; Pat ‘481 claim 8(c)) and an ABM that specifically binds to CD19 (i.e., “an ABM2 that binds specifically to a tumor associated antigen”; Pat
481 claim 8(a)), and an ABM that specifically binds to CD3 (claim 8(b)).
Pat ‘481 does not claim methods of treating proliferative diseases with the binding molecule, or a combination therapy with a second MBM that comprises an anti-CD3 ABM and an anti-CD19 ABM (i.e., instant claim 1).
Wu et al., in the same field of endeavor, teaches anti-CD19/CD3 bispecific antibody blinatumomab for treatment of acute B-cell lymphoid leukemia (ALL; Abstract). Wu et al. teaches that antibodies that target both an tumor-associated antigen (in this case, CD19) and a TCR protein such as CD3 can engage T-cells in a patient to direct them to kill tumor cells (pg. 2, ¶1): “By redirecting unstimulated primary human T cells against CD19-positive lymphoma cells, the bispecific CD19/CD3 antibody fragment showed significant cytotoxic activity at very low concentrations…”.
Wu et al. teaches that this bispecific t-cell engager therapy with blinatumomab reduced tumor growth in a majority of patients (pg. 6, Col. 2, ¶2): “…continuous infusion of blinatumomab to allow T cell recovery. CR or CRh (incomplete hematological recovery) was observed in 25 of 36 patients (69 %), and 22 of 25 responders (88 %) achieved a molecular remission…Median relapse-free survival (RFS) was 7.6 months, with a 9.8-month median overall survival (OS)… These results are encouraging compared to the median OS of 6 months in relapsed ALL with chemotherapy…”
Wu et al. teaches: 1) anti-CD19xCD3 T-cell engagers are a promising treatment for patients with ALL, and 2) blinatumomab is one of these bispecific T-cell engagers that is a promising therapeutic to treat ALL.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have used the CD2xCD3xCD19 trispecific MBM (i.e. “a first MBM” that comprises an ABM that specifically binds to CD2 and an ABM that binds to the tumor-associated antigen CD19) of Pat ‘481 in a method of treating ALL in combination with blinatumomab (i.e., the limitations of instant claims 1, 5, and 11) with a reasonable expectation of success, as Wu et al. teaches that therapeutics that specifically target both CD3 and CD19 are effective in treating ALL, which is the MBM claimed by Pat ‘481. One would have been motivated to make this change to develop a combined therapy with both T-cell engagers to treat ALL. Additionally, it is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; the idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Claims 42-45 and 52 are included because ALL is a leukemia, which is a hematological malignancy/cancer.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by Pat ‘481 in view of Wu et al., especially in absence to evidence of the contrary.
Claims 1, 5, 11, 42-45, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 11, 13, 40, 41, 95, 135, 136, 142, 146, 150, 165, 187, 188-190, 192, and 197 of copending Application No. 18/944,885 (herein App ‘885) in view of Wu et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘885 claims anti-CD19 antibodies (claim 1), as well as multispecific binding molecules comprising an ABM that specifically binds to CD2 (i.e., “an ABM1”), the anti-CD19 antibody (i.e., “a tumor-associated antigen” and “an ABM2”), and a binding moiety that specifically binds to a component of the TCR complex (claim 41).
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘885 in view of Wu et al for the same reasons discussed for Pat ‘481 supra. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 11, 42-45, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 169-207 of copending Application No. 18/035470 (herein App ‘470) in view of Wu et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘470 claims anti-CD19 antibodies (claim 169), as well as multispecific binding molecules comprising an ABM that specifically binds to CD2 (i.e., “an ABM1”; App’470 claim 186(c)), the anti-CD19 antibody (i.e., “a tumor-associated antigen” and “an ABM2”; App ‘470 claim 186(a)), and a binding moiety that specifically binds to CD3 (claim 186(b) and 188).
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘470 in view of Wu et al for the same reasons discussed for Pat ‘481 supra. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 11, 42-45, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 121-157 of copending Application No. 18/035472 (herein App ‘472) in view of Wu et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘472 claims anti-CD19 antibodies (claim 121), as well as multispecific binding molecules comprising an ABM that specifically binds to CD2 (i.e., “an ABM1”; App’472 claim 131(i)), the anti-CD19 antibody (i.e., “a tumor-associated antigen” and “an ABM2”; App ‘472 claim 126), and a binding moiety that specifically binds to CD3 (claim 126).
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘472 in view of Wu et al for the same reasons discussed for Pat ‘481 supra. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 11, and 42-45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 93, 139, 145, 147-149, 151, 152, 165, 170, 172, 173, 186-190, 194, 197-202 of copending Application No. 17/595637 (herein App ‘637) in view of Hipp et al. (Leukemia. 2017 Oct;31(10):2278. doi: 10.1038/leu.2017.219. Epub 2017 Jul 28). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘637 claims MBMs comprising an ABM that binds specifically to CD2 (i.e., “an AMB1 that specifically binds to CD2; App ‘637 claim 1(b)), an ABM that binds to BCMA (i.e., “an AMB2 that specifically binds to a human tumor-associated antigen”; App ‘637 claim 1(a)). App ‘637 additionally clams methods of treating BCMA-expressing cancer comprising administration of the MBM (claim 189), including B-cell malignancies such as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and multiple myeloma (claim 194).
App ‘637 does not claim methods of treating multiple myeloma comprising administration of the claimed MBM and a second MBM that has an ABM specific for BCMA, and another ABM that is specific for CD3 (i.e., the limitations of instant claim 1, 5, 11, and 42-45).
Hipp et al., in the same field of endeavor, teaches methods of treating multiple myeloma comprising administration of a BCMA/CD3 bispecific T-cell engager (Abstract). Hipp et al. teaches that the T-cell engager BI 936909 is a MBM comprising an ABM (i.e., “an ABM4”) that specifically binds to CD3 (i.e., “a component of human TCR”), and a second ABM (i.e., “an ABM5”) that binds specifically to BCMA (Abstract).
Hipp et al. further teaches a method of treating multiple myeloma in a patient comprising administration of the BI 936909 T-cell engager (“In vivo activity of BI 836909” Section), which led to significant reduction in multiple myeloma tumor progression (“In vivo activity of BI 836909” Section and Figure 6): “BI 836909 eradicates established xenograft tumors and significantly prolongs survival.”
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have combined the methods of treating multiple myeloma claimed by App ‘637 and taught by Hipp et al. with a reasonable expectation of success, as both references concert multispecific binding molecules for the treatment of BCMA expressing cancers such as multiple myeloma that one with ordinary skill in the art would appreciate could be combined. One would have been motivated to make this change for the purposes of treating multiple myeloma with both agents. Additionally, it is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; the idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘637 in view of Hipp et al. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 11, 13, 42-45, 52, and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 22, 23, 28, 34, 35, 40, 41, 44, 45, and 47-50 of copending Application No. 17/311315 (herein App ‘315) in view of Lu et al. (Angew Chem Int Ed Engl. 2014 Sep 8;53(37):9841-5. doi: 10.1002/anie.201405353. Epub 2014 Jul 23). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘315 claims MBMs comprising an ABM that binds specifically to CD2 (i.e., “an ABM1”; App ‘315 claim 34(c)), another ABM that specifically binds to a tumor-associated antigen (i.e., “an AMB2”; App ‘315 claim 34(b)), and an ABM that specifically binds to CD3 (claim 34(a)). App ‘315 additionally claims the MBM wherein the TAA is CLL-1 (claim 40).
App ‘315 does not claim methods of treating proliferative diseases with the trispecific binding molecule, or a combination therapy with a second MBM that comprises an anti-CD3 ABM and an anti-CLL-1 ABM (i.e., instant claims 1, 5, 11, and 13), or methods of treating AML comprising administration of the combination therapy (i.e., the limitations of instant claims 42-45, 52, and 53).
Lu et al., in the same field of endeavor, teaches (Abstract): “[h]uman C-type lectin-like molecule-1 (CLL1) is a recently identified myeloid lineage restricted cell surface marker, which is overexpressed in over 90% of AML patient myeloid blasts and in leukemic stem cells.” Lu et al. additionally teaches antibodies targeting CLL-1 can be used as a therapy to target and eliminate AML cells (Introduction): “a monoclonal antibody targeting CLL1 has demonstrated therapeutic potential against AML cell lines via complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC)”.
Lu et al. further teaches a bispecific T-cell engager comprising an antigen binding domain that specifically binds to CD3 (i.e., “an ABM4 that binds specifically to a component of a human TCR”), and an antigen binding domain that specifically binds to CLL-1 (i.e., “an ABM5 that binds specifically to a human tumor-associated antigen”) is an effective therapeutic to treat a subject with AML (Introduction and Figure 4): “Using this same method, we now report the synthesis of a novel CLL-1 targeting BiFab, αCLL1-αCD3, and a comparison of its in vitro and in vivo activity to a similarly constructed CD33 targeting BiFab, αCD33-αCD3. We show that although both BiFabs are cytotoxic toward AML cell lines and patient-derived cells, the αCLL1-αCD3 bispecific antibody has increased potency in vitro, and in contrast to αCD33-αCD3, completely eliminates established tumors in a subcutaneous xenograft mouse model using the human AML cell line U937.”
Lu et al. teaches (last ¶ of Discussion): “…this study demonstrates the potential of CLL1 as an AML target antigen, and our αCLL1-αCD3 as a promising T cell engaging bispecific agent”.
Lu et al. teaches: 1) anti-CLL1xCD3 T-cell engagers are a promising treatment for patients with AML, and 2) Lu et al. teaches a method of treating AML comprising administration of an antiCLL1xCD3 bispecific T-cell engager.
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the instant application, to have used the CD2xCD3xCLL-1 trispecific MBM (i.e. “a first MBM” that comprises an ABM that specifically binds to CD2 and an ABM that binds to the tumor-associated antigen CLL1) of App ‘315 in a method of treating AML in combination with the anti-CLL1xCD3 bispecific T-cell engager taught by Lu et al. (i.e., the limitations of instant claims 1, 5, 11, 13, 42-45, 52, and 53) with a reasonable expectation of success, as Lu et al. teaches that therapeutics that specifically target both CD3 and CLL1 are effective in treating AML, which is the MBM claimed by App ‘315. One would have been motivated to make this change to develop a combined therapy with both T-cell engagers to treat AML. Additionally, it is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; the idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘315 in view of Lu et al., especially in absence to evidence of the contrary. This is a provisional double patenting rejection.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641