DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 241-243, 246-248, 251-259, and 261-282 have been cancelled; claims 239-240, 244-245, 249-250, and 260 have been amended; and claims 283-286 have been newly added, as requested in the amendment filed on May 19, 2023. Following the amendment, claims 239-240, 244-245, 249-250, 260, and 283-286 are pending in the instant application.
Claims 239-240, 244-245, 249-250, 260, and 283-286 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 17/199,205, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. While the application above discloses SEQ ID NOs:1-8 (LCDRs, HCDRs, LC variable, and HC variable domains) it does not disclose the full sequences corresponding to instant SEQ ID NOs:30-33 (full LC and HC sequences). Table 1 is also is also different between the priority document(s) and so the instant application should be redefined as a CIP. As such, no priority is given beyond the PCT filing date since only the PCT teaches the instantly claimed sequences. As such, claims 239-240, 244-245, 249-250, 260, and 283-286 have an effective filing date of June 01, 2021 corresponding to PCT/US2021/035290.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/28/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because some of the figure labels and text are blurry and difficult to read. See, for example, Figs. 15 and 22-28. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the terms BiTE (Page 2), BLAST (Paragraph 0061), Cremophor EL (Paragraph 00235), Tween (Paragraph 00240), Alexa Fluor, CytoFLEX, Flowjo, and FACSDiva (all Paragraph 00242), for example, which are trade names or marks used in commerce, have 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
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
Here, claims 283-286 will be interpreted under 35 U.S.C. 112(f) as they recite means for binding CD3 without providing any structure required for the function. Therefore, “means for binding CD3” is interpreted as any CD3 binding domain disclosed in the instant specification and equivalents thereof (e.g., those disclosed in the prior art).
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 239, 244, 249, 260, 283, and 285-286 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims above are drawn to a genus of antibodies, including monoclonal antibodies, defined by fewer than the required six CDRs for the types of antibodies made. See Table 1. Thus, one must go to the specification to evaluate the amount of representative complete CDR set species taught to represent the claimed genera. When one goes to the instant specification to identify a representative number of species to define the claimed genera with respect to antibodies with six CDRs they find only one CDR set, that of Table 1 on Page 32. Thus, Applicant’s attempt to define their antibody genus with only a single species. Even if the prior art is aware of additional antibodies, or Applicant has variants of the one set taught (which would only be highly related species), the totality of known antibodies would not be representative of each entire genus for the reasons discussed below.
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus antibody with specific epitope, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the antibodies claimed can have any CDR set, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” One of skill in this art cannot envision the structure of any other antibodies that function with at least a partial CDR set as claimed, other than the single species provided by Applicant. Therefore, since only a single species is provided to represent these genera, the claims reciting the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. One species is certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Since only a single species is taught within the claimed genera above, those that bind the recited epitopes, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe these genera.
Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract).
Thus, while applicant has described one species within each of the genera recited, and the art may provide more, each genus is very large and would encompass antibody structures (CDR sets) that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the antibody structures encompassed by the claimed genera only defined by function. Any future antibody structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite all complete parental CDRs of the species disclosed since it is these structures together that are required to bind the recited antigen.
Claims 239, 244, 249, 260, 283, and 285-286 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 antibodies in which the binding domain is defined by all six complete parental CDRs and the treatment of cancers with surface display of specified HLA-E/neoantigen complexes (see claim 260), does not reasonably provide enablement for similar antibodies in which any binding domain is defined by less than six complete parental CDRs, or methods of preventing any cancer, or for treating with a cancer present but lacking surface display of the complexes above. 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 or use the invention commensurate in scope with these claims.
The Breadth of the Claims
Claims 239, 244, and 249 are extremely broad, being drawn to a monoclonal antibody or antigen binding fragment thereof comprising SEQ ID NOs: 30, 32, and 33, respectively.
Claim 283 is extremely broad, being drawn to a BiTE comprising the heavy chain of SEQ ID NO: 30 and a means for binding CD3.
Claims 260 and 285-286 incorporate/depend from claims 239, 244, 249, and/or 283 and as such are equally broad in scope.
As such, the general scope of the invention is monoclonal antibodies and antigen binding fragments thereof generally comprising a heavy chain of the above-identified sequences, and thus are antibodies defined by only three CDRs (i.e., HCDRs 1-3).
It is further noted with regard to claim 286, that the claim is drawn to the treatment of any HLA-E expressing cancer. With respect to “treatment” it is noted that “treatment” at Paragraph 0059 is identified as including prophylactic treatment, i.e., preventing a disease. As such, the treatment of cancer as recited in claim 286 includes, by definition, preventing cancer.
The State/Level of Unpredictability in the Prior Art
With respect to each antibody-based antigen binding domain recited, the state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine or humanized or human antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibody fragments of the instant claims as broadly as claimed. This occurs at least at claim 260 and 285-286 which are written in such a way that just any antigen binding fragment can be taken from the antibody structure of other claims. This includes any fragment with a partial CDR set and even as little as a single CDR which all contribute to antigen binding but would not be expected to do so in isolation. Thus, these claims a rejected here.
With respect to the lack of enablement of all claims that recite an antibody with one variable region without reciting the target antigen, Portolano (The Journal of Immunology, Vol. 150, No. 3, Pg. 880-887, 1993) teaches that so long as one of ordinary skill has possession of a functional variable region, known to function in the context of a full antibody with six CDRs to bind a target antigen, then, so long as that antigen is also recited, a complementary variable region can be identified in an antibody library that can be used with the first variable region to create an antibody with six CDRs that can bind the same antigen as the parent antibody. This was demonstrated with an anti-thyroid peroxidase (TPO) antibody called SP1.2 (Abstract). Klimka (British Journal of Cancer (2000) 83: 252-260) describes a screening process using a mouse VL and a human VH library with CDR3 and FR4 retained from the mouse VH (Abstract). After obtaining antibodies, the VH was screened against a human VL library to obtain antibodies that bound antigen (Abstract). Each round of the two rounds of chain shuffling used by Klimka requires a functional, full variable domain to identify a complementary variable domain (Pg. 253, Column 2). A similar approach was taught by Beiboer (J. Mol. Biol. (2000) 296:833-849) who describes a screening process using the entire mouse heavy chain and a human light chain library. After obtaining antibodies, one VL was combined with a human VH library with the CDR3 of the mouse retained. Antibodies capable of binding antigen were obtained (Abstract). Thus, identifying an antibody using a library approach without at least one defined variable region that is known to function in an antibody context to bind the desired target is unpredictable and would require undue experimentation. It is suggested that Applicant amend the claims to recite the target antigen in all independent claims.
Cancer treatment is highly unpredictable. Even though the EGFR was identified in some cancers as a drug target, the in vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer in vivo (i.e., in the body). Numerous EGFR inhibitors that showed promising in vitro activity failed for a variety of reasons. These included poor pharmacokinetics due to poor absorption or rapid metabolism ( or both), undesirable drug-drug interactions, drug toxicity due to drug binding onto healthy cells, drug toxicity due to binding onto other receptors, and metabolite toxicity. Some drug candidates were limited by one or more of these shortcomings, further underscoring the unpredictable nature of cancer treatment. OSI Pharmaceuticals , LLc, v. Apotex Inc, 939 F.3d 1375, 2019.
The state of the art at the time of filing was such that the functionality of an anti-tumor antibody was dependent on both its action on the intended target and whether or not the modulation of said target had an effect on any particular cancer cell. Baxevanis (Expert Opinion: Drug Discovery, Vol. 3, No. 4, Pg. 441-452, 2008) teaches that, depending on the epitope against which an antibody is directed, antibody-antigen binding may neutralize circulating targets or cell surface receptors (Pg. 444, Column 1, Paragraph, first full). They teach that presently available monoclonal antibodies (mAbs) are directed against molecular targets that are expressed on tumor cells or play an important role in the tumor microenvironment (Pg. 444, Column 1, Paragraph, first full; Table 1). Table 1 lists currently available antibodies for use in clinical oncology and illustrates that each antibody has a specific target (Table 1, Column 2) and a specific set of cancers for which it has therapeutic utility (Table 1, Column 4). Taken together, the art does not recognize a single antibody that is an effective therapy against all tumors.
To further illustrate this point, Baxevanis goes on to explain the functionality of the more commonly used therapeutic antibodies. Trastuzumab targets the receptor HER-2 (HER-2/neu) which is overexpressed in some breast cancers and so is a viable treatment for said breast cancers (Pg. 444, Column 2, Lines 19-24). The basis of this variability in treatment response is due to the fact that the growth inhibitory effect of anti-HER-2 is dependent on the extent of HER-2 overexpression (pg. 443, Column 1, Paragraph, first partial). Because only a portion of breast cancer patients overexpress HER-2 and respond to trastuzumab, the selection of suitable patients is important (Pg. 445, Column 1, Lines 13-15).
Rituximab is an antibody against CD20 antigen, which is expressed on most B cells including B-cell lymphomas (Pg. 445, Column 1, Lines 36-38). Therefore, it is used to treat B-cell lymphomas (Pg. 444, Table 1). It has been used to treat patients with relapsed or refractory low-grade non-Hodgkin's lymphoma (a B-cell lymphoma) (Pg. 445, Column 1, Lines 41-50).
In contrast to trastuzumab and rituximab, some therapeutic antibodies show efficacy in treating multiple cancers. This stems from the fact that their target antigen is associated with multiple cancers. Cetuximab is an anti-EGFR antibody (Pg. 445, Column 1, Lines 19-20). EGFR is overexpressed in many epithelial cell tumors (Pg. 445, Column 1, Lines 20-21). The association of EGFR overexpression with multiple cell types gives cetuximab a broader therapeutic applicability than trastuzumab (Pg. 444, Table 1) as it is used to treat both renal and head and neck cancers.
As a final point, the art also recognizes that the function of the therapeutic antibody must correlate with an effect on its target conducive to tumor growth inhibition or tumor lysis, resulting in patient benefit. Anti-HER-2 antibodies, like Trastuzumab, disrupt HER-2 catalytic activity (Pg. 443, Column 1, Paragraph, first partial, Sentence, ultimate; Table 1, Column 3, (S) referring to decreased protein signaling (activity); and Pg. 444, Column 2, Lines 19-22). Cetuximab also inhibits its target’s activity as it prevents EGFR dimerization and subsequent activation via phosphorylation (Pg. 445, Column 1, Lines 23-25). Since both HER-2 and EGFR activity support growth of cancer cells in which they are overexpressed, their inhibition is therapeutic to patients. Rituximab causes tumor cell lysis by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (Pg. 445, Column 1, Lines 38-39) and so its therapeutic benefit is provided by specifically inducing cancer cell death.
The teachings of Baxevanis discussed above underline the requirement of a link between an inhibitory antibody’s target and specific cancers to make therapy of said cancer predictable to one of ordinary skill in the art. Therefore, it would be unpredictable that the recited antibodies would have any therapeutic effect on a tumor not expressing the full target complexes comprising HLA-E and a neoantigen, barring the presentation of evidence by Applicant. Indeed, the specificity of the antibody appears to be for the complex and it does not bind HLA-E alone. See the citations above in the specification. It is well-known in the art that cancers are made up of heterogeneous cells with varying proteomes.
Hoon (US2006/0115832, published 07/01/2006) teaches metastatic melanoma tumors are heterogeneous in melanoma marker expression (0128). Linke (US2006/0275844, published 12/07/2006) teaches that tumor tissue tends to be heterogeneous and predictive value of markers requires validation (0239). Diamandis (US2012/0178111, published 07/12/2012) teaches that lung cancer is a heterogeneous disease (0202). Kipps (US2011/0190157, published 08/04/2011) teaches protein biomarkers differ between aggressive CLL and indolent CLL B cells (0053).
With respect to cancer prevention, no material has been found to date that has been shown to or would be expected to prevent cancer, and there is no working example, prior art, or any evidence that would provide the skilled artisan with any predictable guidance to use the claimed invention. It would be reasonable to conclude the claimed invention is not enabled.
Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Further, a preventive administration also must assume that the therapeutic will be safe and tolerable for anyone susceptible to the disease.
The vaccine art teaches that compositions comprising some tumor associated antigens are effective in treatment of cancer through generation of immunogenic response to the tumor antigen (see for example, Komenaka et Al., Clinics in Dermatology, 2004, Vol. 22, Pg. 251-265, specifically page 257). However, nowhere in the art does it show that tumor antigens are effective at preventing cancer. Evans et Al. (Q. J. Med 1999: 92: 299-307) teach that vaccines against cancer are not fully established, and it is stated that adjuvant therapy to prevent or delay disease still needs experimentation. Evans et Al. further state that such cancer vaccines are at best used as a therapeutic and not as a prophylactic and that “the notion that cancer vaccines will replace standard therapeutic strategies in malignant disease still belongs to the realm of fiction” (see page 303 last paragraph).
In some cases, it is known that certain cancers arise from a single cause. This cause can be viral as in the case of cervical cancer, caused predominantly by persistent cervical infection with human papillomavirus (HPV) (Schiffman et Al., The New England Journal of Medicine, Vo. 353, No. 20, Pg. 2101-2104, 2005). Schiffman et Al. teach that primary prevention through vaccination against HPV might be possible in young women (Pg. 2101, Column 3, Paragraph, first partial). However, they also teach that vaccine evaluations are ongoing (Pg. 2103, Column 3, Paragraph, first full). In addition, the most promising vaccines designed against HPV types 16 and 18 would only prevent 70 percent of cervical cancer cases at best (Pg. 2103, Column 2, Paragraph, first full). Therefore, there is still no vaccine that can definitively prevent a cancer. Current evidence points only to the potential of future prophylactic agents.
The art of small molecule chemotherapeutics teaches that some molecules successful at treating cancers can also reduce risk. Cuzick et Al. (The Lancet, Vol. 361, Pg. 296-300, 2003) teach that tamoxifen can reduce the risk of ER-positive breast cancer but cannot be recommended as a preventive agent (Pg. 299, Column 2, Paragraph, first). The reason it cannot be recommended centers around the need for continued research into specific subgroups of high-risk but healthy women for whom the risk-benefit ratio is sufficiently positive to recommend prophylactic tamoxifen treatment (Pg. 299, Column 2, Paragraph, first).
With respect to peptide-based cancer prevention agents, the art currently does not recognize a definitive example though promising candidates are present. Hernandez-Ledesma (Peptides, Vol. 30, Pg. 426-430, 2009) teaches that lunasin, a peptide discovered in soy has demonstrated cancer-preventative capacity in vitro and mouse models (Abstract). The authors define it as a perfect candidate to exert an in vivo cancer-preventive activity but more research is required to establish it in this role (Pg. 429, Column 2, Paragraph, first partial).
Therefore, the art has only recognized the treatment of a cancer.
The Amount of Direction Provided
At Page 32 of the Specification, Table 1 is provided which recites human monoclonal antibodies that bind the complexes identified in claim 260, including the CDRs, the VH and VL, and some variant full-length heavy chains to provide varying functions to full-length antibodies. See SEQ ID Nos. 30, 32, and 33). It is clear from the table that the recited antibodies of the instant claims must comprise six CDRs to function. In addition, as discussed below, claims reciting one full variable region and the target antigen are also considered enabled. However, not all claims require at least six complete parental CDRs for each antigen binding domain or at least one full variable domain with the antigen target recited. Furthermore, it is clear to PHOSITA that cancer treatment requires cancer cells that express not only HLA-E as in claim 286 currently, but also this HLA complexed with the peptides supra, said complex being the tumor target of the recited antibodies. See the title of Table 1 and Paragraph 00282 (Example 8) for discussion on ABX0020 specificity, for example. Also, as identified above, treatment is defined to encompass prevention (Paragraph 0059).
The Existence of Working Examples
As identified above, Example 8 of the instant specification (Paragraph 00282) demonstrates that exemplary antibody ABX0020 does not bind HLA-E alone, nor HLA-type I peptides (i.e., neoantigens) alone; binding of ABX0020 was only observed in the presence of peptide/HLA-E complexes.
Thus, considering the breadth of the claims, the state and level of unpredictability in the art, and the lack of direction and working examples provided by the inventor, claims 239, 244, 249, 260, 283, and 285-286 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as pertains to scope of enablement.
Double Patenting - 35 USC § 101 - Statutory
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 239, 249, 260, 283, and 285-286 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 239, 244, 280, 303, and 306-308 of copending Application No. 18/000,493 (reference application).
SEQ ID NOs: 30 and 33 of the instant application are 100% matches to reference application SEQ ID NOs: 20 and 21, respectively, which are recited in reference application claims 239 and 244. The copending claims also identify an identical target of the recited antibodies; reference application claim 280 recites that the antibodies selectively bind to a complex comprising an HLA-E and neoantigen comprising SEQ ID NO: 18 (100% match to instant SEQ ID NO: 18). Furthermore, the copending claims provide for the same BiTE of the instant claims (reference application claim 303 and 306), the same pharmaceutical composition (reference application claim 307), and the same method of treating cancer (reference application claim 308). Since the copending claims teach the instant claims with no difference in scope this rejection is set forth.
This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Double Patenting - Non-Statutory
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 239, 244, 249, 260, 283, and 286 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,981,997 in view of non-patent literature by Saunders (Frontiers in Immunology, 2019, 10(1296), 1-20; herein after referred to as Saunders) and non-patent literature by Xu et. al. (Cellular Immunology, 2000, 200, 16-26).
Patented claims 1-3 and 6-8 disclose monoclonal antibodies, or antigen binding fragments thereof, that selectively bind a complex comprising an HLA-E and a peptide that comprises SEQ ID NO: 18 wherein the antibody comprises (i) LCDRs corresponding to SEQ ID NOs: 1-3 and HCDRs corresponding to SEQ ID NOs: 4-6 or (ii) VL corresponding to SEQ ID NO: 7 and VH corresponding to SEQ ID NO: 8. It is specifically noted that the patented HCDRs and VH are a 100% match to the HCDRs and VH comprised within instant SEQ ID NOs: 30, 32, and 33 and patented SEQ ID NO: 18 is a 100% match to instant SEQ ID NO: 18. Patented claims 4-5 and 9-10 disclose bispecific T cell engagers comprising the monoclonal antibodies wherein the bispecific T cell engagers bind to CD3 protein associated with a T cell receptor. Patented claims 11-13 generally disclose methods of treating cancer that express HLA-E.
The patented claims do not recite full length heavy and light chains as in instant claims.
However, , it is noted that the specification of the patent discloses species that include full-length antibodies wherein antibody variable regions were subcloned into mammalian expression vectors, with matching human kappa light-chain constant region (pFUSE2ss- CLIg-hK, Invivogen) and human IgG1 constant region (pFUSEss-CHIg-hG1, Invivogen) sequences (Paragraph 00161). When one puts the patented VH and VL domains into these contexts they arrive at instantly claimed antibody species recited in instant claims 239, 244, and 249.
Thus, the patented claims in view of the species of the specification falling under the scope of the patented claims, and thus defining said scope, on their own render obvious instant claims 239, 260, 283, and 286. However, with respect to instant claims 244 and 249, it is noted that neither patented claims nor species disclosed in the specification falling under the scope of the patented claims disclose monoclonal antibodies wherein the heavy chain constant region comprises LALA mutations (as in instant SEQ ID NO: 32) or DLE mutations (as in instant SEQ ID NO: 33). This deficiency is remedied by Saunders.
Saunders