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 4/21/2023, is acknowledged.
Claims 26-43 are cancelled.
Claims 1-25 are currently pending.
Claims 1 and 8 are independent claims.
Election/Restrictions
Applicants’ election without traverse of Group I, claims 1-16 and 19, directed to a BTLA binding agent; and the Species of: i) the binding agent comprising CDRH1-3 of SEQ ID NO: 201-203 and CDRL1-3 comprising SEQ ID NO: 204-206, the VH sequences of SEQ ID NO: 144 and 151-153, and the VL sequence of SEQ ID NO: 174; and ii) an IgG4 antibody; filed on 6/01/2026, is acknowledged.
As stated in the Restriction Requirement mailed on 12/03/2025, the inventions of Groups I (claims 1-16 and 19) and Group III (claims 20-23) have unity of invention.
As stated in Applicant’s remarks filed 6/01/2026, the antibody species recited in claims 8-14 do not read on the elected species of antibody. The elected species of antibody has the CDRH1 of SEQ ID NO: 195 wherein X1 is T and X2 is W, the CDRH2 of SEQ ID NO: 196 wherein X1 is absent, X2 is D, X3 is D, and X4 is V, the CDRH3 of SEQ ID NO: 197 wherein X1 is S, X2 is N, X3 is F, X4 is R, and X5 is W, the CDRL1 of SEQ ID NO: 198 wherein X1 is V, X2 is S, and X3 is H, the CDRL2 of SEQ ID NO: 199 wherein X1 is A, X2 is T, and X3 is L, and the CDRL3 of SEQ ID NO: 200 wherein X1 is L and X2 is W.
Claims 8-14, 17, 18, 24, and 25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or Species.
Claims 1-7, 15, 16, and 19-23 are under examination drawn to the elected species of BTLA binding agent.
Priority
Applicant’s claim for the benefit of a prior-filed US provisional patent application 63/192,984 filed on May 25, 2021, and U.S. provisional patent application 63/105,067 filed on October 23, 2020, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 4/21/2023, 5/07/2024, 8/14/2025, and 10/24/2025 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 use of the terms:
Biacore™ (¶[0130]);
KinExA® (¶[0132]);
AffiPURE® (¶[0132]);
Accutase™ (¶[0132], [0143], [0149], [0156]);
Histopaque™ (¶[0137]);
Alexa Fluor® (¶[0137], [0140]);
Brilliant Violet™ (¶[0137], [0140]);
DyLight® (¶[0137], [0138], [0143]);
NovoCytet® (¶[0137], [0140]);
Graphpad Prism® (¶[0137], [0140], [0143], [0149], [0153], [0156], [0160], [0164], [0168], [0172], [0177]);
BD Pharm Lyse™ (¶[0140]);
Steady-Glo® (¶[0149], [0160]);
PathHunter® (¶[0164], [0166]-[0168], [0171], [0172]); and
QuickPlex ® (¶[0181]);
which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
U.S. Provisional Application 63/105,067, which the instant application claims the benefit of as a priority document, discloses that the antibody clone 6G3 is also known as ANB032 (¶[0156]): “…curves with 500, 50, 5, 035, & 0 ug/ml ANB032 (6G3) were diluted in assay buffer…”. Also see Fig 16 (corresponding to instant Fig 16).
The instant specification discloses that the 6G3/ANB032 antibody clone has the CDRH1-3 and CDRL1-3 of SEQ ID NO: 201-206, respectively, or the elected species of antibody. The instant specification discloses that 6G3 was humanized to generate the VH and VL sequences of SEQ ID NO: 144 and 174, respectively (Example 1), which are elected species as well.
Claim Objections
Claims 1-7, 15, 16 and 19 are objected to because of the following informalities:
Claims 1-7, 15, 16 and 19 recite the acronym “BTLA”, which is not a readily recognized acronyms in the art, such as “DNA” for 5’-deoxyribonucleic acid. Please define the acronym “BTLA” when it is first used in the claims.
Claim 1 is additionally objected to because the claim recites elements (a), (b), and (c) in two instances, one for the light chain and one for the heavy chain CDR listings. Please amend the claim to recite (a)-(f) instead of (a)-(c) twice to resolve any potential clarity issues.
Claim 19 is additionally objected to because the claim recites, in part, an unelected invention (“…or nucleic acid encoding the same…”).
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 1-7, 15, 16, 19, and 20-23 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claims 1 and 6 recites “a CDRH1 comprising”, “a CDRH2 comprising”, “a CDRH3 comprising”, “a CDRL1 comprising”, “a CDRL2 comprising”, and “a CDRL3 comprising”, each followed by an amino acid sequence. Claim 7 recites “comprising”, followed by “an immunoglobulin heavy chain variable region of” and “an immunoglobulin light chain variable region of”, each followed by an amino acid sequence.
The claims lack written description support because the claims use open language “comprising” and, for example, “a CDRH1 comprising” followed by an amino acid sequence, the phrase results in an antibody comprising the claimed antibody or any portion of the claimed sequence. The claim terminology, for example, of “a CDRH1 comprising” followed by an amino acid sequence, and “an immunoglobulin heavy chain variable region of” followed by an amino acid sequence does not place size limits on the VH/VL/CDRs, but rather reads on any portion of the claimed VH/ VL/ CDRs of SEQ ID NO. The VH/VL/CDRs are generic with respect to size, encompassing anything from dimers on up to the full size of the claimed SEQ ID NOs.
Dependent claims 2-5, 7, 15, 16, and 19-23 do not resolve the issues and are also rejected under 35 U.S.C. § 112(a) Written Description.
To resolve this issue, it is recommended to amend the claims to recite “the” in place of “a”/”an” in the recited instances supra to place size limits on the claimed sequences. For example, “a CDRH1 comprising SEQ ID NO: 201” recited in claim 6 can be amended to “the CDRH1 comprising SEQ ID NO: 201”.
Claims 1-5, 7, 15, 16, and 19-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for BTLA binding agents comprising the 6 CDR sequences, or the VH and VL sequences, of the antibody clones disclosed in instant Tables 2 and 3 with the function of “BTLA-binding agent”, and methods of modulating BTLA signaling in a mammal comprising administration of these antibody clone structures, does not reasonably provide enablement for a broad genus of antibody structures with a partial structure at best and the function of “BTLA-binding agent”, or methods of modulating BTLA signaling in a mammal comprising administration of a broad genus of antibody structure with a partial structure at best or a nucleic acid encoding the genus of structures. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
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:
Claims 1, 15, 16, and 19-23 encompass a broad genus of binding agents with a partial structure at best (claims 1, 15, 16 and 19), or methods of modulating BTLA signaling in a mammal comprising administration of a broad genus of antibodies with a partial structure at best and the function of “BTLA-binding agent”. For example, using the variable CDR sequences recited in claim 1, the claims encompass over [(2*13)*(2*11*11*11)*(2*2*13*2*14)*(2*2*3)*(2*2*12)*(2*11)] ≈ 1.27x1012 structures with this function.
Claims 2 and 3 recite the CDR sequences of claim 1 with additional partial sequence structures for the heavy chain, all with the function of “BTLA-binding agent”. Claim 2 encompasses (2*2*13*2*11*11*11*2*3*2*2*2*2*2*2*13*2*14) = 19,348,353,024 different heavy chain structures paired with ((2*2*3)*(2*2*12)*(2*11)) = 12,672 light chain structures for a total of approximately 2.45x1014 structures with the claimed function of “BTLA-binding agent”. Instant claim 3 recites the heavy chain polypeptide sequence comprising any of SEQ ID NO: 43-156 and variants with up to 10% sequence variation, including in the CDR regions. The elected species of VH, SEQ ID NO: 141, is 125 residues long and therefore claim 3 encompasses variants of this VH structure with up to 12 amino acid substitutions, including in the CDR regions critical for binding, all with the function of “BTLA-binding agent”. The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula:
N
!
*
19
A
N
-
A
!
A
!
Where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. For a polypeptide that is 125 residues in length with 12 allowed substitutions, there would be
125
!
*
19
(
12
)
125
-
12
!
12
!
Which is approximately 9.21x1035 variants for this one recited sequence only, all with the function of “BTLA-binding agent”.
Claims 4 and 5 recite the CDR sequences of claim 1 with additional partial sequence structures for the light chain, all with the function of “BTLA-binding agent”. Claim 4 encompasses (2*2*2*2*3*2*2*12*2*2*11) = 101,376 different light chain structures paired with (2*13)*(2*11*11*11)*(2*2*13*2*14) = 100,772,681 different heavy chain structures for a total of approximately 1.0x1013 structures with the claimed function of “BTLA-binding agent”. Instant claim 5 recites the heavy chain polypeptide sequence comprising any of SEQ ID NO: 157-192 and variants with up to 10% sequence variation, including in the CDR regions. The elected species of VH, SEQ ID NO: 174, is 108 residues long and therefore claim 5 encompasses variants of this VH structure with up to 10 amino acid substitutions, including in the CDR regions critical for binding, which is approximately 9.6x1028 light chain structures alone all with the function of “BTLA-binding agent”.
Claim 7 recites a genus of binding agents comprising the heavy chain of SEQ ID NO: 144 and the light chain of SEQ ID NO: 174 with up to 10% variation in each sequence, which lead to genus of 9.21x1035 heavy chain variants paired with a genus 9.6x1028 light chain variants, all with the function of “BTLA-binding agent”.
Claims 20-23 additionally recite methods of modulating BTLA signaling in a mammal comprising administration of a nucleic acid encoding a broad genus of BTLA binding agent structures described supra.
The specification discloses antibody clones that bind to BTLA (Examples, Tables 1-3). The 6G3 antibody clone structure was demonstrated to block graft-vs-host disease after mice are injected with human PBMCs (Example 15, Fig. 14).
Amount of direction and existence of working examples:
Examples of different antibody structures are disclosed in Tables 1-3 and ¶[0127]. Each of these antibody clone are specific structures, defined by their amino acid sequences especially in the 6 CDR regions critical for antigen binding, with the function of “BTLA-binding agent”. For example, ¶[0127] discloses the CDR sequences of two different humanized anti-BTLA antibody clones isolated from mouse hybridomas:
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348
745
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The antibody clone 6G3 blocked graft-vs-host disease after mice are injected with human PBMCs in vivo (Example 15, Fig. 14, cropped below):
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148
948
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148
948
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The specification further discloses the 6G3 clone also reduces BTLA occupancy and surface expression on T and B cells in vivo (Example 18, Fig. 20):
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858
1220
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Level of predictability, state of prior art, and quantity of experimentation needed:
Regarding the broadly claimed genre of agents with a partial structure at best and the function of “BTLA-blocking agent” (claims 1-5, 7, 15, 16, and 19-23), the claims are directed to agents with a partial structure at best, all with the function of “BTLA-blocking agent”, which includes broad genera of millions to billions of different structures, including antibodies and other polypeptide structures, with the recited function.
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 different examples of anti-BTLA antibody structures with the function of “BTLA-blocking agent” (Tables 1-3, ¶[0127]). These antibody clones are all specific structures, defined by their amino acid sequences which give rise to the function of “BTLA-blocking agent”, especially in the CDR regions critical for antigen binding.
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 class of antibodies with a partial structure at best with all with the function of “BTLA-blocking agent”. This function not only includes binding to BTLA (claims 1-5, 7, 15, 16, and 19-23), but also having a specific function in vivo to modulate BTLA signaling in a mammal (claims 20-23).
The instant claims are directed to classes of polypeptides 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 antibody structure to determine whether or not it met the function limitations of “BTLA-blocking agent”. 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 other polypeptide structures would have the function of “BTLA-blocking agent”. The only structure-function relationship guidance the specification provides is to disclose individual examples of anti-BTLA antibody structures with these 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 inhibitory antibodies that bind to BTLA and modulate BTLA signaling in a mammal and a limited number of species with defined structures (e.g. amino acid sequences) to support an entire genus of diverse and structurally unrelated modulatory antibody structures. Yet the instant specification does not provide sufficient guidance and directions as to the structural features of the polypeptide structures and the correlation between the structure and the desired antigen binding and inhibitory function.
Additionally, the instant application encompasses (but does not exemplify) fragments and CDRs modification of up to 10% (deletion/addition/substitution) to the claimed CDRs of SEQ ID NO: 43-156 and 157-192 (claim 1), the heavy chain sequences of SEQ ID NO: 43-156 (claim 3 and 7), or the light chain sequences of SEQ ID NO: 157-192 (claims 5 and 7). There is no teaching identifying what amino acids can be varied within the VH-CDRs and/or VL-CDRs antibody regions and still retain the function of binding BTLA. Brown et al. (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g., 6CDR's) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VLCDRs or VHCDRs regions of the disclosed antibody and the retention of a specific binding antibody that binds the BTLA to satisfy the WD requirement for the claims.
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 claimed methods of modulating BTLA signaling in a mammal comprising administration of a nucleic acid encoding a BTLA binding agent (claims 20-23), the instant specification does not disclose and examples of methods of modulating BTLA signaling in a mammal comprising administration of nucleic acid encoding a BTLA antibody, only administration of the antibody itself. Neither the instant specification nor the prior provide sufficient guidance to use such a method of modulating signaling comprising administration of a nucleic acid. Undue experimentation would be required by one with ordinary skill in the art to use the claimed method of modulating BTLA signaling.
The specification does not reasonably provide enablement to make and use the invention of instant claims 1-5, 7, 15, 16, and 19-23. The specification does enable one with ordinary skill to make the antibody clone discussed supra.
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.
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 1-5, 15, 16, and 19-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite in the recitation “the heavy chain and light chain sequences listed in Tables 2, 3, 4, and 5” because it fails to point out what is included or excluded by the claim language. Tables 2-5 are subject to changes via amendments even after allowance. Such amendments would change the scope of claim 4 According to MPEP § 2173.05(s):
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Incorporation by reference to Tables, Figures, and Examples as in this case, is a necessity doctrine, not for Applicants’ convenience. See Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). Appropriate action is required.
Dependent claims 2-5, 15, 16, and 19-23 do not resolve the issue in claim 1 and are also rejected as indefinite. It is recommended to amend claim 1 to recite specific sequences in place of referencing a table in the specification to resolve this issue.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 6 are rejected under 35 U.S.C. 102(a)(1)/(2) as being anticipated by Murphy et al. (U.S. PGPub 20110236401).
Claim 1 recites anti-BTLA binding agents comprising the CDRH1-3 and CDRL1-3 of SEQ ID NO: 201-206, respectively (i.e., the elected species of antibody).
Murphy et al. teaches antibodies that modulate the interaction between BTLA and HVEM ([0014]): “…the present invention provides BTLA antibodies, sometimes referred to herein as BTLA blocking antibodies. A BTLA antibody of the invention is capable of specifically binding to a BTLA protein and is capable of reducing the binding of the BTLA protein to an HVEM protein…”
Murphy et al. additionally teaches the anti-BTLA antibody 6G3 ([0032]): “…a BTLA antibody is selected from the group consisting of ‘6A6’, ‘6F7’, ‘6G3’…” Also see [0373]:
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286
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Therefore, Murphy et al. teaches a mouse IgG1 anti-BTLA antibody clone 6G3, which is interpreted to inherently contain the CDRH1-3 and CDRL1-3 sequences of SEQ ID NO: 201-206, respectively, anticipating the limitations of instant claims 1 and 6.
Although the reference does not teach the sequences for the CDRs from the 6G3 monoclonal antibody, these are intrinsic properties of the 6G3 antibody. Also, it is an inherent property of the 6G3 immunoglobulin light and heavy chains to bind to the same antigen as the original antibody. Therefore, the light and heavy chain CDRs instantly claimed are unpatentable over the prior art as the sequences are intrinsic properties of the antibody.
The issues presented herein are akin to the holding in In re Crish, 73 USPQ2d 1364 (CAFC 2004) where the Federal Circuit held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.”
Like the references in Crish, the prior art of Murphy et al. reference discloses a material containing the same CDR sequences recited in the claims. It is undisputed that Murphy et al. discloses an antibody that contains the amino acids recited in Applicant’s claims. That disclosure is anticipatory, even if it was not until the present application that Applicants characterized Mab 6G3 by its amino acid sequences. However, it is apparent that Murphy et al. teaches a mouse version of 6G3, while the instantly claimed application claims VH and VL sequences from humanized versions of 6G3, which would have the same CDR sequences but different framework sequences.
The reference teachings anticipate the instantly 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, 6, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Murphy et al. (U.S. PGPub 20110236401, supra).
The teachings of Murphy et al. have been discussed in the 35 U.S.C. § 102 rejection supra. Murphy et al. additionally teaches (¶[0296]): “[t]he antibody may be an IgG such as IgGl, IgG2, IgG3 or IgG4; or IgM, IgA, IgE or IgD isotype. The constant domain of the antibody heavy chain may be selected depending upon the effector function desired.”
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the teachings of Murphy et al. to generate IgG4 version of the 3G6 antibody (i.e., the limitations of instant claim 1, 6, and 15) with a reasonable expectation of success, as Murphy et al. teaches that the antibody may be in the IgG4 format. One would have been motivated to do so to generate an antibody with a desired effector function, as taught by Murphy et al. Additionally, it is considered optimization or routine experimentation to generate different antibody isotypes of the same monoclonal antibody, for example to change the effector function of the antibody, as taught by Murphy 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 reference, especially in the absence of evidence to the contrary.
Claims 1, 6, 15, and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Murphy et al. (supra) in view of del Rio et al. (Transplantation. 2011 Nov 27;92(10):1085-93. doi: 10.1097/TP.0b013e3182339d4a).
The teachings of Murphy et al. have been discussed in the 35 U.S.C. § 103 rejection supra. Murphy et al. additionally teaches methods of modulating immune responses, such as the responses of B and T lymphocytes (¶[0341]), including administration of pharmaceutical compositions comprising an anti-BTLA antibody and an acceptable carrier (¶[0326]): “…bioactive agents of the present invention are administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo… including a therapeutically active amount of a BTLA antibody, optionally in combination with an additional therapeutic agent as described herein, and a pharmaceutically acceptable carrier.”
Murphy et al. does not explicitly teach methods of modulating BTLA signaling in a mammal with a disorder such as graft v. host disease comprising administration of pharmaceutical compositions comprising the 6G3 antibody and an acceptable carrier (i.e., the limitations of instant claims 19-23).
del Rio et al., in the same field of endeavor, teaches that administration of an anti-BTLA antibody can lead to a significant reduction of graft v. host disease in a murine model (Abstract): “…administration of an anti-BTLA monoclonal antibody leads to significant reduction of donor anti-host allogeneic immune response against bone marrow and thymus during the acute phase of graft versus host reaction in a parent into nonirradiated F1 murine model of alloreactivity…”
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the teachings of Murphy et al. in view of del Rio et al. to have tried to administer the 6G3 antibody in a pharmaceutical compositions with an acceptable carrier to modulate BTLA signaling in a mammal such as a mouse to treat graft v. host disease (i.e., the limitations of instant claims 19-23) with a reasonable expectation of success, as del Rio et al. teaches that anti-BTLA antibodies can be administered to mammals to treat graft v host disease and methods of doing so (“Parent into non-irradiated F1 acute GvHR murine model” Section in Supplemental Methods). One would have been motivated to do so for the purposes of trying to treat graft v host disease in a mammal via modulating BTLA signaling with the 6G3 antibody.
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 1, 6, 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Murphy et al. (supra) in view of Ahmad et al. (Clin Dev Immunol. 2012;2012:980250. doi: 10.1155/2012/980250. Epub 2012 Mar 15).
The teachings of Murphy et al. are discussed in the 35 U.S.C. § 103 supra. Murphy et al. does not teach 6G3 in an scFv version (the limitations of instant claim 16).
Ahmad et al., in the same field of endeavor, teaches antibodies can be engineered in a single-chain format, or an scFv (pg. 2, Section 3): “An antibody in scFv (single chain fragment variable) (Figure 1) format consists of variable regions of heavy (VH) and light (VL) chains, which are joined together by a flexible peptide linker that can be easily expressed in functional form in E. coli, allowing protein engineering to improve the properties of scFv (single chain fragment variable) such as increase of affinity and alteration of specificity”
Ahmad et al. additionally teaches benefits of scFvs over full-length antibodies (pg. 6-7, Section 8): “An antibody in scFv (single-chain fragment variable) format retained the complete antigen-binding capability…The small antigen-binding molecule of scFv (single chain fragment variable) antibodies could offer several advantages over a whole antibody molecule in therapeutic applications [20, 22]. The smaller fragments allow these molecules to penetrate more rapidly and evenly to tumors and other tissue in comparison to the whole antibodies [20, 121]. As these fragments have more rapid clearance from blood, they can be coupled with drugs and radionuclides in order to result in low exposure of the healthy tissue [19, 122, 123]. Besides that, they also found that there was no uptake of the scFv (single-chain fragment variable) by the kidney and they could efficiently localize to the tumors…”
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 anti-BTLA antibodies such as 6G3 taught by Murphy et al. in view of Ahmad et al. to generate scFv versions of 6G3, as Ahmad teaches the general structure of an scFv that can be applied to antibodies such as those taught by Murphy et al. One would be motivated to make this change for the purposes of generating scFv versions of 6G3 that have advantages over the full-length antibody, such as increased tissue penetration and low exposure of coupled drugs/radionucleotides to healthy tissue, as taught by Ahmad 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 15, 19, and 20-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-21 and 23-25 of copending Application No. 18/859958 (App ‘958) in view of Murphy et al. (U.S. PGPub 20110236401, supra).
App ‘958 claims anti-BTLA antibodies comprising the VH and VL of SEQ ID NO: 144 and 174, respectively (claim 18). SEQ ID NO: 144 of Pat ‘958 is 100% identical to instant SEQ ID NO: 144:
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SEQ ID NO: 174 is 100% identical to instant SEQ ID NO: 174:
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Therefore, App ‘958 claims the elected species of antibody, which are the limitations of instant claims 1-7. App ‘958 additionally claims methods of modulating BTLA signaling in a human (i.e., “a mammal”) comprising administration of the anti-BTLA antibody (claim 9), wherein the disorder is responsive to BTLA modulation (claim 10), wherein the disorder is an autoimmune or inflammatory disease (claim 11), wherein the disease is rheumatoid arthritis (claim 12), which are the limitations of instant claims 20-23.
App does not claim the anti-BTLA antibody as an IgG4 isotype, or in a pharmaceutical composition with an acceptable carrier (i.e., the limitations of instant claims 15 and 19).
Murphy et al., in the same field of endeavor, teaches methods of modulating immune responses, such as the responses of B and T lymphocytes (¶[0341]), including administration of pharmaceutical compositions comprising an anti-BTLA antibody and an acceptable carrier (¶[0326]): “…bioactive agents of the present invention are administered to subjects in a biologically compatible form suitable for pharmaceutical administration in vivo… including a therapeutically active amount of a BTLA antibody, optionally in combination with an additional therapeutic agent as described herein, and a pharmaceutically acceptable carrier.”
Murphy et al. additionally teaches (¶[0296]): “[t]he antibody may be an IgG such as IgGl, IgG2, IgG3 or IgG4; or IgM, IgA, IgE or IgD isotype. The constant domain of the antibody heavy chain may be selected depending upon the effector function desired.”
It would have been obvious to one with ordinary skill in the art to have modified the invention of App ‘958 in view of Murphy et al. to use the claimed method of treatment with the anti-BTLA antibody in a pharmaceutical compositions with an acceptable carrier with a reasonable expectation of success, as Murphy eta l. teaches BTLA antibodies can be formulated in such compositions. One would have been motivated to make this change for the purposes of using an acceptable pharmaceutical composition in the methods of modulating BTLA signaling claimed by App ‘958.
Additionally, it would have been obvious to one with ordinary skill in the art to have generated IgG4 version of the antibody claimed by App ‘958 with a reasonable expectation of success, as Murphy et al. teaches that the antibody may be in the IgG4 format. One would have been motivated to do so to generate an antibody with a desired effector function, as taught by Murphy et al. Furthermore, it is considered optimization or routine experimentation to generate different antibody isotypes of the same monoclonal antibody, for example to change the effector function of the antibody, as taught by Murphy et al.
Therefore, the invention encompassed by the instant application is a prima facie obvious variant of the invention claimed by App ‘958 in view of Murphy et al. This is a provisional double patenting rejection.
Claim 16 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-23 and 23-25 of copending Application No. 18/859958 (App ‘958, supra) in view of Murphy et al. (supra), as applied to claims 1-7, 15, and 19-23 above, and further in view of Ahmad et al. (Clin Dev Immunol. 2012;2012:980250. doi: 10.1155/2012/980250. Epub 2012 Mar 15, supra).
The combined teachings of App ‘958 in view of Murphy et al. have been discussed supra. The combined teachings do not teach an scFv version of the anti-BTLA antibody (i.e., the limitations of instant claim 16).
The invention encompassed by the instant application is a prima facie obvious variant of the invention claimed by App ‘958 in view of Murphy et al., and further in view of Ahmad et al. for the same reasons discussed in the 35 U.S.C. § 103 rejection supra. 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
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