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 1-234 are canceled.
Claims 235-252 are under examination on the merits.
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 disclosures of the prior-filed applications, 62/957024, 63/070596, and PCT/US2020/067543, fail 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. The PCT application has the same disclosure as the instant case. Therefore, it also fails the written description and enablement requirements for all reasons infra the instant disclosure fails them with respect to the instant claims. This leaves the chain of priority broken for said claims.
Claims 235, 237, 238-240, 242, and 243 do not fail the requirements of 112a currently and so receive the U.S effective filing date of 01/03/2020.
Claims 236, 241, and 244-252 all receive the U.S. effective filing date of 06/30/2022 as they fail at least one of the 112a requirements as discussed infra.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement (IDS) submitted on 07/08/2024 is being considered by the examiner. Any strikethrough is owed to lack of date.
Drawings
The drawings are objected to because Figures 38A-40B, 42, 55A-H, 80-86, 96, 101A-103B, 104, 105B, 106B, and 108A-C are all illegible.
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 amendments to the drawings filed 10/07/2024 and specification filed 10/07/2024 are objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows:
In the drawings, Figures 109E, 110C, and 110J were not previously presented and so are new matter. In the specification, all added figure legends for these three figures are necessarily also new matter.
Applicant is required to cancel the new matter in the reply to this Office Action.
The use of the terms: DARPINs (0334), AFFIBODY (0334), and DUTAMAB (0662), each of which is a trade name or a mark used in commerce, has been noted in this application. Each 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 Objections
Claim 251 is objected to because of the following informalities: For clarity, the phrase “in need thereof” should be replaced with “having cancer”.
Claim 250 is objected to since comprises in lines 2 and 4 should be comprise. The same objection is made for claims 248-249.
Appropriate correction is required.
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.
Claim 247 is 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.
This claim recites IL-21 comprising a sequence at least 95% identical to SEQ ID NO: 2193. However, no variants that meet any percent identity to this sequence are taught in the instant disclosure and shown to function. Thus, owed to recitation of this claim element, the claim fails the written description requirement.
“[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.
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 IL-21 variants can have a wide range of mutations/truncations, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any other peptides with the required function other than the species provided by Applicant. Therefore, since only a species is provided to represent the genus, the claims encompassing the same clearly fail the written description requirement.
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. Thus, pairing cytokine with the variant claimed does not help in describing it.
“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).
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 the 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 (SEQ ID NO: 2193) is certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing peptides and then selecting those peptides 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 peptides 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). Absent the conserved structure provided by a core inhibitory peptide sequence, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what any peptide with a particular set of functional properties would look like structurally.
Since only a species of IL-21 is taught within the recited genus above, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe such a massive genus. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe said genus.
Owed to the variation among the peptides of the genus as broadly as currently claimed, it is very difficult to provide adequate representation of the functionally defined peptide genus. There is unlikely to be any structure (subsequence) shared by the entire genus, for example. If there is a subsequence common to all or some of Applicant’s species, then the claims should recite that as part of the peptide genus to provide adequate representation of the actual disclosed/possessed group. Also, the disclosure of one group of highly related peptides does not guide one of skill to the next peptide of the genus with said function. Finding another said peptide would require mutation and it is well-known in this art that mutation of peptides leads to specific function loss.
The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through mutagenesis. Importantly, binding can still occur after mutation, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Thus, while applicant has described a species within the genus recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide structures encompassed by the claimed/recited genus only defined by function (cytokine). Any future peptide 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 entire recited genus of peptides. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
Claims 236, 241, and 244-250 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. This is a new matter rejection.
Each claim below recites limitations not found in the original disclosure and so contain the new matter discussed infra.
Claim 236 recites at least 80% identity to each of the VH listed. However, only as little as 85% was taught in the original disclosure. See for example page 330. The same rejection is made for claim 241 for the same reason.
For claim 244 and its dependents, a specific antibody design is recited. Each design recited contains several structural elements, not all of which are found in any one design taught in the instant disclosure. Therefore, first, one must pick from multiple lists of antibody chain elements and combine them to form each design recited. Picking an element from multiple lists is at best obvious but is not a clear teaching or contemplation of the subject matter. Therefore, each design is rejected here as new matter for not being specifically taught or contemplated in the original disclosure. Furthermore, even if any one of the designs is specifically called out in its entirety in the large disclosure, there would still be a list of possible designs and a list of antibodies that binds TCRbetaV from which to choose and combine elements to arrive at the subject matter of these claims. Again, selecting from two or more lists is at most arriving at an obvious antibody molecule/design. However, no one antibody that can be constructed from selected from such two or more lists is specifically taught or originally contemplated by the original disclosure. Therefore, for these reasons, these claims fail the written description requirement for containing new matter. This same argument is made for claim 245, 246, 247, 248, 249, and 250.
The are additional elements in claims 245-250 which are new matter as well. All recitations therein of 80% identity to the VH and VL region recited are new matter as they were not originally taught and certainly not taught in these specific designs. The same arguments are made for the recitations of 85% identity to all sequence identifiers such modifies in claims 248-250 as well as its combination with any proviso.
Also claims 248-250 recite or any combination thereof. The designs recited prior to this are already new matter but even if they were not, the examiner finds no contemplated of just any combination thereof. Thus, all elements (3) in these claims are additionally new matter.
Taken all together, due to the claims above reciting at least one embodiment not originally taught or contemplated, they are rejected here for having new matter. Though the original disclosure may be sufficient to render the claims above obvious, this is not the same as their full scopes being originally taught and rather proves that they were not taught as they needed to be made obvious from the disclosure.
Claims 245-252 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 cytokines defined by full sequence known to function, anti-TCRbetaV antibodies comprising six parental CDRs known to function, and methods of treating cancer with a functional bispecific antibody against TCRbetaV and a tumor associated antigen or methods of treating a TCRbetaV+ cancer with a functional, monospecific anti-TCRbetaV antibody, does not reasonably provide enablement for use of mutated cytokines, antibodies with mutated CDRs, or methods of treating cancer with an anti-TCRbetaV with no logical mechanism of action against the same. Similarly, the specification enables expansion of TCRbetaV+ T cells with an anti-TCRbetaV antibody but does not enable the same for just any immune cell. 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 is a composition comprising an anti-TCRbetaV binding region which can have mutated VH and VL regions or methods of using the same to treat cancer.
The nature of the invention is an anti-TCRbetaV antibody which can be used with an anti-tumor associated antigen (TAA) antibody in a bispecific format to crosslink T cells and tumor cells.
The level of skill of one skilled in this art is high.
The specification teaches throughout antibodies against TCRbetaV which have six CDRs. See Table 13 for the antibody embodiment claimed. Thus, any antibody with mutated versions of these CDRs would not be expected to bind antigen as discussed infra. With respect to treating cancer, it only stands to reason the antibody must be able to bind the target cancer and so be TCRbetaV+ or be part of a multispecific antibody that binds tumor and T cells (Pg. 282 and Example 4). With respect to immune cell population expansion with the antibody claimed, only TCRbetaV+ T cells could be expanded therewith, not just any T cell subset. See 0108, Pg. 279, and Example 3.
With respect to cytokine mutation, claim 247 recites mutant variants of IL-21 by stating at least 95% identity to SEQ ID NO. 2193. Such mutant variants of IL-21 encompass those not made or tested and such are not enabled. Thus, the claim is not enabled to its full scope and is rejected here.
The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, conservative replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J of Cell Bio. 111:2129-2138, 1990). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al. Molecular and Cellular Biology 8:1247-1252, 1988). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (Proceedings of the National Academy of Sciences, U.S.A., Vol. 88, Pg. 2658-2662, 1991) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide.
This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, Vol. 13, Pg. 475-484, 2000) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract).
In another case, Huang (The Journal of Biological Chemistry, Vol. 272, No. 43, Pg. 27155-27159, 1997) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important.
Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nature Genetics, Vol. 18, Pg. 150-154, 1998) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Human Molecular Genetics, Vol. 18, No. 18, Pg. 3353-3364, 2009) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment.
In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (The Journal of Biological Chemistry, Vol. 272, Pg. 21201-21206, 1997) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first).
Since the art teaches that it is unpredictable whether or not peptide variants will function as their parent, and the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the cytokine product of instant claims as broadly as they are currently claimed.
With respect to CDR mutation, it is unpredictable in effect. Claims 245-250 recite antibody domains with mutated CDRs. This is because the VH and VL recited need not be the same as recited in claim 235. Also, the VH and VL of these claims is recited with at least 80% identity to sequence identifiers and this allows for CDR mutation as the CDRs have not been fixed in these domains by a parent claim. Thus, these claims are rejected here for reciting antibody domains with mutated parental CDRs.
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 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 mutated antibodies of the instant claims as broadly as claimed.
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. 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.
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies comprising fewer than all six parental CDRs or comprising mutated versions thereof, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
With respect to treating just any cancer with an anti-TCRbetaV antibody, this is unpredictable even with a functional antibody. 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 ( [**2]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.
Essentially, most cancers will not be treatable with the antibody as it is not predictable that expansion of T cell subsets actually treats any disease alone. Indeed, cancers have numerous ways to evade the immune system. Rather, there must be a nexus between the recited antibody and tumor cell biology to make said treatment predictable. In other words, either the cancer cell must express the antibody target TCRbetaV or the antibody must be within a multispecific antibody that binds a tumor associated antigen (TAA) as well.
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.
With respect to treating a patient with just any cancer 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). Taken together, as broadly as cancer is currently claimed, claim 251 is not enabled to its full scope and is rejected here.
By logical extension of the above discussion over Baxevanis and the art teaching differential expression of proteins in different cells, it is clear that claim 252 is not enabled for expansion of just any immune cell. Rather, it must be an immune cell that is TCRbetaV+ so that the antibody can bind and also one that would respond with expansion to TCR agonism, which is a T cell. Thus, the only predictable expansion method using the claimed antibody is one that expands TCRbetaV+ T cells.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claim(s) 236, 241, and 252 are rejected under 35 U.S.C. 102a1 as being anticipated by Loew (WO2020/142672, published 07/09/2020).
Loew teaches murine MPB2D4 antibody that binds TCRbV 20-1 and comprises SEQ ID NO:107 as VH and SEQ ID NO. 106 as VL (Pg. 183). These sequences are instant SEQ ID Nos. 1112 and 1111 respectively. They provide methods of expanding T cells ex vivo by contacting said cells with antibodies against TCRbetaV regions (Abstract). Thus, not only is the antibody above a composition of matter but also at once envisaged by PHOSITA as a composition with at least excipient for administration to the T cell supra.
Thus, they clearly anticipate the claims above.
Claim(s) 236, 241, and 251 are rejected under 35 U.S.C. 102a2 and 102a1 as being anticipated by Powell (WO2021/155112, published 08/05/2021 with priority to 01/29/2020).
Powell teaches a CAR comprising a domain that binds TCRbetaV (Abstract). The domain against the TCRbetaV can comprise SEQ ID Nos. 81 and 85 (Pg. 4, Paragraphs, fifth-sixth and Pg. 29, Paragraph, fifth) which are instant SEQ ID Nos. 1112 and 1111 respectively. This CAR is a composition of matter and they also teach its use in modified T cells to treat cancer (Pg. 66, Paragraph, third and Pg. 100, Paragraph, final and all of examples 6-7) as a pharmaceutical composition (Pg. 66, Paragraph, fourth) in dosages for human administration (Pg. 68, Paragraph, second). The examples above make clear humans are the target patient population of the treatment method as human cell lines/cells are used in the studies.
Thus, they clearly anticipate the claims above.
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 235-243 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 156, 166, 172, 178 of copending Application No. 17/402322 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copening claims recite the structures of instant claims.
Of note, SEQ ID Nos. 1111-1112 are identical between the two applications.
Copending claim 173 recites compositions with anti TCRbetaV moieties comprising SEQ ID NO. 1112 and 1111. Copending claim 178 recites a composition with an antibody with the same CDRs as in instant claim 235. This antibody can be a Fab or scFv according to copending claim 166. Thus, the copending claims clearly teach instant claims 235-241 and so they are rejected here and render obvious instant claims 242-243 as Fab and scFv each are a clear choice of antibody format for the claimed antibody.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 235-243 and 251-252 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 14-16, 19-20, 29, 36-37, 49, and 56-57 of copending Application No. 17/759679 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims recite elements instantly claimed, rendering them obvious.
Of note, SEQ ID Nos. 81 and 85 of the copending application are or contain instant SEQ ID Nos. 1112 and 1111 respectively.
Copending claim 1 recites a nucleic acid encoding a CAR that binds TCRbetaV and the binding domain thereof can be Fab or scFv (copending claim 2) and said binding domain can comprise the CDRs and instant V-regions of SEQ ID NO. 1111 and 1112 as the copending claims say the CAR can have SEQ ID NO. 81 and 85 as domains (copending claims 5-6 and 18-20). Copending claims 29 and 36-37 teach a method of treating cancer by administering a T cel comprising the CAR above. Copending claims 56-57 teach a method of treating cancer with an antibody with the V-regions above. These copending claims clearly render obvious the instant claims above as they recite the instantly claimed antibody in multiple contexts and a method of treating cancer therewith as CAR or antibody, both of said methods requiring a composition of these active agents as is standard practice in this art for administering CAR-cells and antibodies to patients. These patients will obviously be human as copending claim 3 recites human TCR regions. With respect to instant claim 252, this expansion will inherently occur in the method of treating of the copending claims as all steps of the instant claim are met in the obvious treatment method above.
Thus, the copending claims render all instant claims above obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 235-242 and 251-252 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 136, 143-144, 154-158, 166-167 of copending Application No. 18/173995 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims teach the instant claims or render them obvious as discussed infra.
Of note, SEQ ID Nos. 1111-1112 of the copending application are identical to those sequence identifier of the instant case.
Copending claims 143-144 recites a composition with antigen binding domains wherein one can comprise SEQ ID Nos. 1111 and 1112. Copending claims 152-158 make clear that the molecule with said binding domain can have two Fc regions and the binding domain can be an scFv. Copending claim 166 teaches a pharmaceutical composition with the molecule and copending claim 167 teaches a method of treating cancer therewith. Thus, the copending claims render obvious a composition with the binding domain of instant claims and its use in treating cancer. The treated subject will obviously be human as that is the type of target protein inherently bound by the binding domain above (0357 of copending specification) and the type of cancer antigens targeted as well by the molecule of the copending claims (0218). See also the fact that the CDRs of the antibody of the copending claims are used for humanization in Table 13. Thus, the scope of the method for treating cancer of the copending claims clearly encompasses human treatment as clarified by the copending specification. The method of instant claims 252 will inherently occur as all its method steps are met in the obvious method of treating cancer from the copending claims.
Thus, the instant claims above are obvious from the copending claim set and are rejected here.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/Michael Allen/Primary Examiner, Art Unit 1642
Prosecution Insights