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 .
Election/Restriction
Applicant’s election without traverse of Invention I, in the reply filed on 09JUN2025 is acknowledged.
Claims 87-89 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species. Election was made without traverse in the reply filed on 09JUN2025.
Claim Status
Claims 1-69 have been cancelled.
Claims 70-89 are new.
Claims 70-89 are pending in the instant application.
Claims 87-89 are withdrawn as being drawn to a nonelected invention and/or species.
Claims 70-86 are examined on the merits.
Priority
The present application claims priority under 35 USC §119(e), which claims benefit of US Provisional Patent Application No. PCT/US2020/043264, filed 23JUL2020 and US Provisional Patent Application No. 62/878069, filed 24JUL2019. Applicant’s claim for the benefit of prior-filed applications is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 21JAN2022 and 26JAN2024 is/are acknowledged and the references cited therein have been considered.
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.
Enablement
Claims 70-86 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Scope of the claim:
In the instance of claim 70, the nature of the invention is drawn to a method of treating a cell proliferative disorder, comprising administering a therapeutically effective amount of essentially any CD63 agonist, wherein the CD63 agonist is administered to the subject to enhance a T cell response to abnormally proliferating cells of the cell proliferative disorder, which is not fully enabled. Specifically, the broadest claim is not enabled because:
The breadth of which CD63 agonist encompasses (i.e., screening of all molecules that binds CD63 and triggers cellular activity);
The lack of support in the specification and working examples (i.e., only two anti-CD63 agonist antibody clones are used to support any CD63 agonist);
The predictability in the prior art that not all anti-CD63 antibodies are able to act as agonists; and
The undue experimentation to use the invention.
Direction provided by the inventor and existence of working examples:
The specification discloses that a CD63 agonist is defined as an agent determined to have activity in agonizing CD63, wherein a screening assay is determined whether a CD63 binding agent is a CD63 agonist (p 6, lines 6-7). Working examples 1 and 2 of the specification disclose, the use of anti-CD63 (MX-49.129.5 or MA5-24169 clones) in combination with anti-CD3 (i.e., OKT3) are able to increase T cell proliferation and anti-CD63 (MA5-24169 clone) in combination with anti-PD1 potentiates the anti-PD1 treatment. Although, these examples support that two specific anti-CD63 antibody clones are CD63 agonists and when used in combination with a T cell activator such as an anti-CD3 antibody, T cell proliferation is increased and that an anti-CD63 agonist in combination with a CPI results in increased therapeutic efficacy, it is unclear whether the same effect could be observed for any CD63 agonist. Furthermore, it is clear that administration of a CD63 agonist alone neither increases T cell proliferation nor treats cancer in vivo. In this instance, there is no disclosure provided regarding the use of any CD63 agonist or the use of an anti-CD63 agonist alone to increase T cell proliferation or treat cancer.
State of prior art and level of predictability in the art:
Furthermore, the literature teaches that co-stimulatory effects between anti-CD63/anti-CD3 requires interaction with a specific epitope of CD63, wherein the mAb 11C9 clone performed as well as anti-CD28/anti-CD3 in activating T cells, the H6C5 commercially available anti-CD63 antibody clone/anti-CD3 combination was unable to activate T cells (Pfistershammer, et al., J Immuno, 2004, 173, 6000-6008, see entire document, specifically see p 6006, col 2). Therefore, the literature supports the necessity to screen CD63 binding agents for CD63 agonist activity.
Quantity of experimentation needed to make or use the invention based on the disclosure:
Thus, one skilled in the art would be unable to use the method of treating a cell proliferative disorder, comprising administering a therapeutically effective amount of essentially any CD63 agonist and without co-administration of a T cell activating therapeutic. Therefore, the implementation of the invention in view of the breadth of variables (i.e., screening CD63 binders to determine CD63 agonist status), the level of predictability in the art, and the lack of direction provided in the specification and working examples, would require undue experimentation for one of ordinary skill in the art to use the method of treating a cell proliferative disorder.
Written Description
Claims 70-86 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.
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, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
The teachings of the specification and the claimed invention:
Applicant has broadly claimed a method of treating a cell proliferative disorder, comprising administering a therapeutically effective amount of essentially any CD63 agonist, wherein the CD63 agonist is administered to the subject to enhance a T cell response to abnormally proliferating cells of the cell proliferative disorder. The broadest claims do not require the CD63 agonist to have any function apart from being an agent that agonizes CD63 and upon administration treating a cell proliferation disease. No claims recite any specific or particular structure of the CD63 agonist that gives rise to the specific treatment functions upon administration to a subject.
To support such broad claims, the specification teaches a CD63 agonist is defined as an agent determined to have activity in agonizing CD63, wherein a screening assay is determined whether a CD63 binding agent is a CD63 agonist (p 6, lines 6-7). Although the claims are drawn to essentially any agonist, the experimental data teach the use of anti-CD63 (MX-49.129.5 or MA5-24169 clones) in combination with anti-CD3 (i.e., OKT3) are able to increase T cell proliferation and anti-CD63 (MA5-24169 clone) in combination with anti-PD1 potentiates the anti-PD1 treatment.. For example, working example 1 teaches two specific anti-CD63 antibody clones are CD63 agonists and when used in combination with a T cell activator such as an anti-CD3 antibody, T cell proliferation is increased and working example 3 teaches that an anti-CD63 agonist in combination with a CPI results in increased therapeutic efficacy compared to CPI alone or CD63 alone.
The state of the prior art:
With regard to CD63 agonists, the literature supports the necessity to screen CD63 binding agents for CD63 agonist activity. For example, the literature teaches that co-stimulatory effects between anti-CD63/anti-CD3 requires interaction with a specific epitope of CD63, wherein the mAb 11C9 clone/anti-CD3 combination performed as well as the known anti-CD28/anti-CD3 in activating T cells, while the H6C5 commercially available anti-CD63 antibody clone/anti-CD3 combination was unable to activate T cells (Pfistershammer, et al., J Immuno, 2004, 173, 6000-6008, see entire document, specifically see p 6006, col 2).
Furthermore, artisans are well aware that knowledge of a given antigen (for instance a specific epitope of CD63) provides no information concerning the sequence/structure of antibodies that bind the given antigen or in this instance the ability to function as a CD63 agonist. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It is noted that applicant has not claimed a product, but rather a method of administering a product. However, artisans must reasonably be in possession of a product in order to be in possession of methods of administering said product. As has been discussed above, the broadest claims describe the administered product based upon what it does, such as agonizing CD63. However, as has been made clear by recent court cases as well as USPTO guidance, describing a CD63 agonist simply by what it binds is not sufficient to provide adequate written description for the recited genus, and has been mentioned while in this instance antibodies are members of the genus of binders (see claim 28) it is not limited thereto. Indeed, as taught by Edwards et al., Lescar et al., and Goel et al., the number of potential antibody structures (i.e., sequences) which can bind to the same antigen is literally astronomical, and when it is considered that the agent doing the “binding” can literally be anything including a small molecule, lipid, peptide, protein, nucleotide, etc., the size of the genus of administered reagents grows. As such describing the administered reagent based upon what it binds, where it binds, or its function as an inhibitor fails to necessarily provide a structure that gives rise to the aforementioned properties.
Claim analysis:
In this instance, the prior art supports a specific structure of a CD63 binder that is able to function as a CD63 agonist. As presently written, the claims recite that CD63 agonist functions to agonize CD63. However, the specification fails to disclose representative number of CD63 agonists and the working examples fail to disclose any data indicating that the breadth of structures (other than two specific anti-CD63 antibody clones) encompassed by the language of the instant claims will have the same function (i.e., agonize CD63). Therefore, as presently written, the claimed broad genus of CD63 agonist lacks adequate written description because there does not appear to be any correlation between the structure of the agonist and the ability to agonize CD63. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of CD63 agonist that agonize CD63, at the time the instant application was filed.
Logically, if applicant was not in possession of the agent which is being administered, applicant also was not in possession of methods of administering such reagents at the time the instant application was filed.
Claim Rejections - 35 USC § 103
Claims 70-86 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/185908 (The Translational Genomics Research Institute, et al., 20NOV2014), herein referred to as “’908” and in view of Pfistershammer, et al., (J Immuno, 2004, 173, 6000-6008), herein referred to as “Pfistershammer” and Grywalska, et al., (OncoTarg and Ther, 2018, 11, 6505-6524), herein referred to as “Grywalska.”
‘908 teaches methods of treating cancer (i.e., cell proliferative disorder) comprising administering a therapeutically effective amount of an isolated antibody (i.e., CD63 agonist having a structure of a polypeptide, inclusive of Fab fragments) that binds to a human CD63 protein (see entire document, specifically see claim 12, p 4, lines 8-21) and can be used in combination with an antibody that binds a different antigen (i.e., cocktail) which exhibit synergistic therapeutic effects and may be administered concurrently or sequentially (p 18, line 8 to p 19, line 10).
However, they do not teach: wherein the CD63 agonist is administered to enhance T cell response; or that the CD63 agonist is administered to the subject independent of the level of CD63 expression; or wherein the subject to whom the CD63 agonist is administered is receiving T cell activation therapy; or wherein the T cell activation therapy is immune checkpoint inhibitor therapy; or wherein the immune checkpoint inhibitor is selected from the group consisting of CTLA-4, PD-1, etc., or a combination thereof; or wherein the T cell activator is an agonist of a T cell co-stimulatory receptor; or wherein the agonist of a T cell co-stimulatory receptor is selected from OX40 agonist, etc.; or wherein the T cell activator is an antagonist of a T cell inhibitory signal, a cytokine, etc..
Nevertheless, Pfistershammer teaches anti-CD63 (i.e., mAb 11C9) represents an activation-induced reinforcing element, whose triggering promotes sustained and efficient T cell activation and expansion (i.e., potentiate T cell activation therapy) (see entire document, specifically see abstract section). Specifically, Pfistershammer teaches anti-CD63 in combination with anti-CD3 (i.e., T cell activation therapy) resulted in proliferative T cell rates as strong as the well-established co-stimulatory combination of anti-CD28/anti-CD3, while anti-CD63 alone did not induce any T cell proliferative effects (Fig 6A). Pfistershammer further teaches that T cells stimulated via CD3/CD63 mAbs showed even stronger responses upon restimulation than CD3/CD28 co-stimulated T cells (p 6007, col 1). Additionally, mAb 11C9 (i.e., anti-CD63) in combination with the CD40 ligand (i.e., co-stimulatory receptor and CD40 agonist) resulted in potent costimulatory signal leading to sustained T cell activation (p 6007, col 1). Pfistershammer also teaches that the surface molecule expression of CD63 does not impact or affect T cell activation (i.e., CD63 expression is independent of therapeutic efficacy) (p 6007, col 1).
Furthermore, Grywalska teaches that T cell exhaustion, T cell anergy, decreased phosphorylation of the CD3ζ chain, and inhibitory signaling within the tumor microenvironment can result in T cell dysfunction during cancer treatment (see entire document, specifically Immune evasion in cancer due to T cell dysfunction section). Specifically, T cell anergy or the tolerance of T cells toward specific antigens, may develop due to TCR stimulation without sufficient co-stimulatory signals, or because co-inhibitory signals prevail over co-stimulatory signals in the tumor microenvironment thus resulting in insufficient immune response and therapeutic failure (Immune evasion in cancer due to T cell dysfunction section). Additionally, Grywalska teaches that the interaction of co-stimulatory molecules (i.e., CD28 or for example, CD63) on effector T cells and the ligands for these molecules (i.e., PDL1/PDL2, CD80/CD86, etc.) on APCs or tumor cells directs immune response against tumor cells (Blockade of T cell dysfunction section). Specifically, Grywalska teaches that the interaction between CD28 and CD80/CD86 is crucial for T cell activation; however, if CD80/CD86 bind to CTLA4 instead of CD28, T cell anergy occurs (i.e., insufficient T cell activation and therapeutic failure) (Blockade of T cell dysfunction section). Thus, Grywalska teaches that the use of mAbs against PD1/PDL1, CTLA4, LAG3, TIM3, etc.(i.e., a CPI or antagonist of a T cell inhibitory signal) can increase the therapeutic effectiveness in patients with cancer by boosting immune response in the tumor microenvironment (i.e., potentiating T cell activation) (Blockade of T cell dysfunction section).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating a proliferative disease by administering an anti-CD63 agonist antibody disclosed by ‘908 by further comprising administering a T cell activator, such as anti-CD3 or CD40 agonist or CPI as disclosed by Pfistershammer and Grywalska because the CD63/CD3 and CD63/CD40 combination resulted in strong T cell activation and the use of CPI allows ligands on cancer cells to interact with the co-stimulatory molecules which activates T cells and therefore boosts immune response as well as therapeutic effectiveness. One would have been motivated to do so, given the teachings of ‘908 that the anti-CD63 agonist antibody can be used in combination with an antibody that binds a different antigen (i.e., cocktail) which exhibit synergistic therapeutic effects. There would have been a reasonable expectation of success, given the knowledge that utilization of T cell activation therapy, wherein the therapeutic is anti-CD3, CD40 ligand, or a CPI lead to significant T cell activation, which ultimately results in more effective treatment of a proliferative disease, which in this instance is cancer as taught by Pfistershammer and Grywalska.
Furthermore, something which is old, does not become patentable upon the discovery of a new property. "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). See MPEP §2112(I). While the instant claims are directed towards methods rather than products, the logic is sound that performing the same process steps will yield the same outcomes, even if such outcomes were not previously observed or recognized. In this instance, the method of treating a cell proliferative disorder, comprises one step, administration of a known therapeutic (i.e., CD63 agonist) for treating a cell proliferative disorder in a subject with a cell proliferative disorder (i.e., the same patient population), and therefore subsequent recitations regarding the subject or intended results (i.e., enhanced T cell response) do not make the method patentable. Additionally, as presently recited, none of the instant claims actually require artisans to perform additional active method steps to confirm enhanced T cell response and as such recitations are a statement of intended results that are expected to happen upon completion of the recited single step method of administration rather than results obtained after completion of a second required active method step of measuring. Applicant is reminded that claims are limited by what they actually compel an artisan to do, not what it is implied could be done or what an artisan might consider doing in addition to what is recited as actually being done.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641