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 .
Priority
This application is a continuation of application 16/334,872 filed on 03/20/2019, now U.S. Patent No. 11,976,299. Applicant’s claim for the benefit of a prior-filed application provisional application 62/398,963 filed on 09/23/2016 and PCT/US2017/051981 filed 09/18/2017 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/01/2024 is considered by the examiner.
Drawings
The drawings filed on 04/01/2024 are accepted.
Specification
The specification filed on 04/01/2024 is accepted.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 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.
Claim 1 recites a method of treating or preventing cancer in a patient, the method comprising:
identifying one or more mutated amino acid sequences, each mutated amino acid sequence being encoded by a gene comprising a cancer-specific mutation;
inducing first dendritic cells from a patient to present the one or more mutated amino acid sequences;
co-culturing T cells from the patient with the first dendritic cells;
selecting the one or more mutated amino acid sequences for which the T cells have antigenic specificity; isolating monocytes from the patient;
differentiating the monocytes into second dendritic cells;
inducing the second dendritic cells to present the selected one or more mutated amino acid sequences for which the T cells have antigenic specificity;
maturing the second dendritic cells to provide an isolated population of dendritic cells comprising the matured second dendritic cells which present the selected one or more mutated amino acid sequences for which the T cells have antigenic specificity, wherein CD1Ic and CD86 expression by the matured second dendritic cells is above 70%; and
administering the isolated population of dendritic cells to the patient in an amount effective to treat or prevent cancer in the patient.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,' to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The genus “cancer” is generically recited. The breadth of the claimed genus of cancers reasonably encompasses cancers at different stages, affecting different organ systems, and caused by various mechanisms (e.g., including those not caused by a cancer-specific mutation).
[0071] of the specification recites:
“The cancer may, advantageously, be any cancer, including any of acute
lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone
cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer
of the eye, cancer of the bile duct, cancer of the joints, cancer of the neck, gallbladder,
or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity,
cancer of the vagina, cancer of the vulva, cholangiocarcinoma, cancer of the
endometrium, cancer of the esophagus, chronic lymphocytic leukemia, chronic
myeloid cancer, colon cancer, esophageal cancer, uterine cervical cancer,
gastrointestinal carcinoid tumor, glioma, Hodgkin lymphoma, hypopharynx cancer,
kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma,
melanoma, multiple myeloma, nasopharynx cancer, non-Hodgkin lymphoma, cancer of
the oropharynx, ovarian cancer, cancer of the penis, pancreatic cancer, peritoneum,
omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal
cancer, skin cancer, small intestine cancer, soft tissue cancer, stomach cancer,
testicular cancer, thyroid cancer, cancer of the uterus, ureter cancer, urinary bladder
cancer, solid tumors, and liquid tumors. The following examples further illustrate the
invention but, of course, should not be construed as in any way limiting its scope.”
However, the specification does not provide any working examples of treating or preventing any type of cancer. Rather, the working examples are directed to identifying cancer-specific immunogenic epitopes derived from somatic mutations, DC maturation, and stimulating both CD4 and CD8 T cells, as well as memory, effector, and naive neoantigen specific T cells with DCs loaded with long peptides and minimal epitopes.
The prior art does not teach DC vaccines effectively treating any cancer, nor DC vaccines preventing any cancer.
Rosenberg et al. (Rosenberg, Steven A., and Nicholas P. Restifo. "Adoptive cell transfer as personalized immunotherapy for human cancer." Science 348.6230 (2015): 62-68.) for example, notes the ability to treat common epithelial solid cancers, which account for ~90% of all cancer fatalities, is severely limited by the lack of suitable targets exclusive to cancer (e.g., pg. 68, col 1). Additionally, Rosenberg et al. teaches that “a study of exomic mutation rates in more than 3000 tumor-normal pairs revealed that the frequency of nonsynonymous mutations varied more than 1000-fold across different cancer types (33). Pediatric cancers exhibited mutation frequencies as low as 0.1/Mb, whereas melanomas and lung cancers often exceeded 100 mutations/Mb.” (e.g., pg. 64, col 3). In summary, Rosenberg et al. teaches that not all cancer types may benefit from treatment targeting cancer-specific mutations. Further, Rosenberg et al. does not teach any methods or compositions that prevent cancer.
Further, there is no recitation in the claims or disclosure in the specification for an artisan on the route of administration(s), dose(s), formulation(s), etc. that is necessary/sufficient to treat or prevent cancer. [0063-0064] of the specification recites:
“For purposes of the invention, the amount or dose of the inventive population of dendritic cells or pharmaceutical composition administered (e.g., numbers of dendritic cells when the inventive population of dendritic cells is administered) should be sufficient to effect, e.g., a therapeutic or prophylactic response, in the patient over a reasonable time frame. For example, the dose of the inventive population of dendritic cells or pharmaceutical composition should be sufficient to elicit T cells which bind to a mutated amino acid sequence encoded by a cancer-specific mutation, or treat or prevent cancer in a period of from about 2 hours or longer, e.g., 12 to 24 or more hours, from the time of administration. In certain embodiments, the time period could be even longer. The dose will be determined by the efficacy of the particular inventive population of dendritic cells or pharmaceutical composition administered and the condition of the patient, as well as the body weight of the patient to be treated.
Many assays for determining an administered dose are known in the art. For purposes of the invention, an assay, which comprises comparing the extent to which target cells are lysed or IFN-y is secreted by T cells upon administration of a given dose of such dendritic cells to a mammal among a set of mammals of which is each given a different dose of the dendritic cells, could be used to determine a starting dose to be administered to a patient. The extent to which target cells are lysed or IFN- y is secreted upon administration of a certain dose can be assayed by methods known in the art.”
The specification also recites a wide range of one million to one billion dendritic cells administered per infusion [0066].
The specification provides no guidance on administering T cells to a patient, as recited in claims 14-19.
Claim 11 recites “The method of claim 1, wherein maturing the second dendritic cells comprises maturing the second dendritic cells (i) in the presence of polyI:C, R848, and IFN-gamma and (ii) in the absence of a further dendritic cell stimulating agent.
The claims are broad for reciting a genus of dendritic cell stimulating agents. Currently, the composition is claimed functionally rather than structurally and does not possess any structural limitations. As written, the claims are generic to compositions that have the function of stimulating dendritic cells.
The specification offers little guidance on this genera. [0048] of the specification recites “Further dendritic cell stimulating agents may include, but are not limited to lipopolysaccharide (LPS), CD40L expressing 3T3 cells, IL-1$, IL-6, TNFa, and PGE2.” The specification does not provide further guidance on the structure of a dendritic stimulating agent, or how an artisan is to determine whether an agent qualifies as a dendritic stimulating agent. For example, are IL-4 and GM-CSF, which are added to the DC medium to support DC growth, considered dendritic cell stimulating agents (e.g., [0098])? They are not listed as such in [0048], but functionally may be described as dendritic cell-stimulating.
Claim 1 recites “CD1Ic and CD86 expression by the matured second dendritic cells is above 70%”.
Claim 12 recites “The method of claim 1, wherein the matured second dendritic cells express any one or more of IL-12p70, TNFa, IP-12, MCP-1, MIP-1$, CD80, CD83, CCR7, and HLA- DR.”
Claim 13 recites “The method of claim 1, wherein the matured second dendritic cells express all of IL-12p70, TNFa, IP-12, MCP-1, MIP-1$, CD80, CD83, CCR7, and HLA-DR.
Either these are inherent properties of (that naturally flows from) the method steps of claim 1, or they are not. The claims denote that not all of the structures/method steps of the independent claim are able to achieve the recited property(ies) recited in the dependent claim(s).
To the extent it is not an inherent property (that naturally flows) from the product/method of the independent claim, then something must change. The claim is considered to lack adequate written description for failing to recite the structure/active method step(s) that is necessary and sufficient to cause the claimed method to possess the ability to result in an isolated population of dendritic cells that express any/all of these markers. For example, the dosage of the composition in the method of treating and preventing to be administered is recited at a high level of generality, e.g., no positively recited dosage(s) in any claims, as well as the amounts of agents used int eh method to mature dendritic cells. The claim limitations recited above merely state functional characteristics without providing any indication about how the characteristic is provided. If the characteristic does not follow from (is not an inherent property of) the structure/active method steps recited in the claim, it is unclear whether the claim requires some other structure to be added to the composition to provide the characteristic.
In summary, the specification fails to disclose what structural changes to the method steps of claim 1 is necessary and sufficient to treat or prevent cancer in a subject, result in CD1Ic and CD86 expression by the matured second dendritic cells is above 70%, and result in the matured second dendritic cells express any one or more/all of IL-12p70, TNFa, IP-12, MCP-1, MIP-1$, CD80, CD83, CCR7, and HLA- DR. and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
Claims 1-20 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:
A method of treating cancer caused by a cancer-specific mutation in a patient, the method comprising:
identifying one or more neoantigen-specific mutated amino acid sequences by whole exome, whole genome, or whole transcriptome sequencing, each mutated amino acid sequence being encoded by a gene comprising a cancer-specific mutation derived from somatic mutations;
constructing tandem minigenes (TMG) or synthesizing long peptides (LP) encompassing the one or more neoantigen-specific mutated amino acid sequences;
inducing first dendritic cells from a patient with the TMG or LP to present the one or more mutated neoantigen-specific amino acid sequences;
co-culturing CD4+ and/or CD8+ T cells from the patient with the first dendritic cells to identify the one or more mutated neoantigen-specific amino acid sequences for which the CD4+ and/or CD8+ T cells have antigenic specificity;
isolating monocytes from the patient;
differentiating the monocytes into second dendritic cells;
inducing the second dendritic cells with the TMG or LP to present the selected one or more mutated neoantigen-specific amino acid sequences for which the T cells have antigenic specificity;
maturing the second dendritic cells with poly (I:C), R848, and IFN-y to provide an isolated population of dendritic cells comprising the matured second dendritic cells which present the selected one or more neoantigen-specific mutated amino acid sequences for which the T cells have antigenic specificity,
wherein CD1Ic and CD86 expression by the matured second dendritic cells is above 70%; and
administering the isolated population of dendritic cells to the patient.
does not reasonably provide enablement for:
a method of treating or preventing cancer in a patient, the method comprising:
identifying one or more mutated amino acid sequences, each mutated amino acid sequence being encoded by a gene comprising a cancer-specific mutation;
inducing first dendritic cells from a patient to present the one or more mutated amino acid sequences;
co-culturing T cells from the patient with the first dendritic cells;
selecting the one or more mutated amino acid sequences for which the T cells have antigenic specificity; isolating monocytes from the patient;
differentiating the monocytes into second dendritic cells;
inducing the second dendritic cells to present the selected one or more mutated amino acid sequences for which the T cells have antigenic specificity;
maturing the second dendritic cells to provide an isolated population of dendritic cells comprising the matured second dendritic cells which present the selected one or more mutated amino acid sequences for which the T cells have antigenic specificity, wherein CD1Ic and CD86 expression by the matured second dendritic cells is above 70%; and
administering the isolated population of dendritic cells to the patient in an amount effective to treat or prevent cancer in the patient.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Examiner incorporates herein the analysis discussed above in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
The Breadth of the Claims and The Nature of the Invention
The claims are directed to a method of treating or preventing cancer.
No dose, route of administration, volume, formulation, etc. is recited.
The claims are broad for encompassing a multitude of cancers, including those not caused by cause-specific mutations.
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
The art teaches clinical trials related to treating a select few types of cancer with DC vaccines.
Butterfield, Lisa H. "Dendritic cells in cancer immunotherapy clinical trials: are we making progress?." Frontiers in immunology 4 (2013): 454. is considered relevant prior art for reviewing immunotherapy clinical trials involving dendritic cells. Butterfield teaches “Unlike chemotherapy, immunological vaccines have not followed a linear dose-response effect. Instead, because immunologic vaccines depend on the complex interactions of a large number of variables, many of which are difficult to test: (1) the administration route (s.c., i.d., i.v., i.n.,and more recently, intra-lymphatic, i.l.), (2) minimum immunogenic dose, (3) higher dose effects, (4) vaccination schedule (weekly, monthly, or multiple times in a week or month), (5) immunological adjuvant type, and (6) the existing state of host immunological competence.” (e.g., pg. 2-3, “DC VACCINE COMPLEXITIES”). Butterfield explains that poor clinical outcomes from DC vaccines thus far may be tied to late-stage tumors have potent immune-inhibitory functions, traditional chemotherapies making metastatic patients severely immunocompromised, and bulk tumor mass being too large for the available effector T cell population to infiltrate it and eliminate it efficiently (e.g., pg. 3, col 1). Butterfield notes that DC vaccines for cancer prevention may be a future direction of the field but only cites one study the where a Muc-1 peptide-based vaccine in subjects with advanced colonic adenomas (but not yet colorectal cancer). The results showed that the peptide vaccine was immunogenic in 43% of the subjects and response was inversely correlated with circulating MDSC levels (e.g., pg. 5, “DC FOR CANCER PREVENTION?”). However, these results are not the same as showing cancer prevention.
In summary, the prior art does not teach preventing cancer with DC vaccines, nor that DC vaccines can treat any cancer.
The Existence of Working Examples and The Amount of Direction Provided by the Inventor
The specification as filed does not provide any guidance or examples that would enable a skilled artisan to use the disclosed compound in a method of treating or preventing cancer as claimed.
As discussed in the 112(a) written description rejection above, the instant specification provides no working examples regarding treating or preventing cancer in a patient.
The specification fails to provide any evidence that the method as written can predictably and reliably treat or prevent any type of cancer at any stage. The specification provides limited guidance on dosage, dose schedule, route(s) of administration, etc. an artisan may use to successfully treat or prevent cancer.
Since the quantity of experimentation required to practice the invention as claimed is undetermined, one of skill in the art would have been unable to practice the invention without engaging in undue trial and error experimentation as presented in the specification over the scope claimed. In summary, the specification fails to make up for the deficiencies of the global scientific community.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to necessarily and predictably use the claimed method comprising matured dendritic cells to treat or prevent cancer.
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method commensurate with the scope of the claimed invention.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “identifying one or more mutated amino acid sequences, each mutated amino acid sequence being encoded by a gene comprising a cancer-specific mutation” in lines 2-3, as well as “selecting the one or more mutated amino acid sequences for which the T cells have antigenic specificity” in lines 7-8. It is unclear how identifying the one or more mutated amino acid sequences differs from selecting the one or more mutated amino acid sequences (e.g., if the one or more amino acids sequences have already been identified and a first dendritic cell population has already been induced to present the one or more mutated amino acid sequences, how have the one or more amino acids sequences not already been selected for?). For example, how does one “select” for the one or more mutated sequences? Additionally, this raises the question as to whether “the one or more mutated amino acid sequences for which the T cells have antigen specificity” is the same as “the one or more mutated amino acid sequence” previously recited in claim 1. It would be remedial to clarify in the claim language whether every recitation of “the one or more mutated amino acid sequences” is the same sequence, and how selecting differs from identifying. For examination purposes, identifying the one or more mutated amino acid sequences is interpreted to read on “selecting the one or more mutated amino acid sequences for which the T cells have antigenic specificity”.
Claim 8 recites “wherein the T cells which are co-cultured with the first dendritic cells which present the selected one or more mutated amino acid sequences express any one or more of programmed cell death 1 (PD-1), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), 4-1BB, OX40, and CD107a.” It is unclear when the T cells are required to express one of these markers. For example, must the co-culturing step result in the T cells expressing one of these markers? Can only T cells expressing one of these markers be co-cultured with the dendritic cells? It would be remedial to clarify whether the claim language is intended to recite a result of the co-culturing, or to further limit the T cells used in the claimed method. For examination purposes, the claim language reads on T cells expressing any one of these markers at any point during the method (e.g., before, during, and/or after co-culturing).
Claim 9 recites “The method of claim 1, further comprising sequencing the whole exome, the whole genome, or the whole transcriptome of the cancer cell.” It is unclear when this method step is supposed to occur in the claimed method. Additionally, there is insufficient antecedent basis for “the cancer cell” in the claim. The recitation is indefinite because there is no prior reference to cancer cells in claim 9, and there is nothing implicit in claim 1, from which claim 3 depends upon, that would inherently require cancer cells in the base claim to be. Therefore, the metes and bounds of the claim is not clearly and precisely defined. For examination purposes, claim 9 is interpreted to read on sequencing a cancer cell at any point during the claimed method.
Claim 14 recites “The method according to claim 1, further comprising administering T cells to the patient.” It is unclear when this method step is supposed to occur in the claimed method. For example, can/should the T cells be administered at the same time as the dendritic cells? Before? After? Additionally, what T cells are to be administered? The T cell co-cultured with the first dendritic cells? It would be remedial to specify the order of method steps and what T cells are to be administered. For examination purposes, the claim language is interpreted to read on T cells being administered to the patient at any point.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 20 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 20 recites “The method according to claim 1, wherein the isolated population of dendritic cells is autologous to the patient.”
Claim 1 recites “isolating monocytes from the patient; differentiating the monocytes into second dendritic cells… maturing the second dendritic cells to provide an isolated population of dendritic cells”.
Claim 1 already requires the monocytes, from which the isolated population of dendritic cells are derived, to be from the patient. Autologous by definition means to be derived from the same individual. As such, the recitation of claim 20 fails to further limit base claim 1 from which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102/103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-5, 9, 12, 13, and 20 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Carreno et al. (Carreno, Beatriz M., et al. "A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells." Science 348.6236 (2015): 803-808.—published 05/15/2015).
Regarding claim 1, Carreno et al. teaches a method of treating or preventing cancer in a patient, the method comprising:
identifying one or more mutated amino acid sequences, each mutated amino acid sequence being encoded by a gene comprising a cancer-specific mutation (e.g., “Exome sequencing was performed to identify somatic mutations in tumor samples”) (e.g., pg. 804, col 1; Fig. 1A);
inducing first dendritic cells from a patient (e.g., autologous mDC) to present the one or more mutated amino acid sequences (e.g., Supplementary Materials, pg. 5, “Analysis of T cell responses”);
co-culturing T cells from the patient with the first dendritic cells (e.g., Supplementary Materials, Fig. S4B, Fig. S5 (ex-vivo expansion of neoantigen-specific T cells using autologous DC));
selecting the one or more mutated amino acid sequences for which the T cells have antigenic specificity (e.g., Supplementary Materials, Fig. S4B, Fig. S5 (ex-vivo expansion of neoantigen-specific T cells using autologous DC));
isolating monocytes from the patient (e.g., Supplementary Materials, pg. 4, “DC manufacturing and vaccine”);
differentiating the monocytes into second dendritic cells (e.g., Supplementary Materials, pg. 4, “DC manufacturing and vaccine”);
inducing the second dendritic cells to present the selected one or more mutated amino acid sequences for which the T cells have antigenic specificity (e.g., Supplementary Materials, pg. 4, “DC manufacturing and vaccine”);
maturing the second dendritic cells to provide an isolated population of dendritic cells comprising the matured second dendritic cells which present the selected one or more mutated amino acid sequences for which the T cells have antigenic specificity (e.g., Supplementary Materials, pg. 5, “DC manufacturing and vaccine”); and
administering the isolated population of dendritic cells to the patient in an amount effective to treat or prevent cancer in the patient (e.g., Supplementary Materials, pg. 5, “DC manufacturing and vaccine”).
Carreno et al. is silent on CD11c and CD86 expression by the matured second dendritic cells being above 70%. However, the method taught by Carreno et al. is anticipatory, as Carreno et al. teaches the same active method steps (i.e., structure) as the claimed method. The resulting expression profile of the cells produced by the claimed method does not impart any structural limitations, and instead describes the product produced. Thus, this element is not required to be disclosed or taught by Carreno et al.
Alternatively, the Examiner notes that to generate neoantigen-specific T cell lines using autologous mDC, Cafri et al. referred to the method as described in Beatriz M Carreno, et al., Amino-Terminal Extended Peptide Single-Chain Trimers Are Potent Synthetic Agonists for Memory Human CD8+ T Cells, The Journal of Immunology, Volume 188, Issue 12, June 2012, Pages 5839–5849 (reference 12 of Carreno et al.) for guidance. Carreno et al. also refers to B. M. Carreno, et al. , IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity. J. Clin. Invest. 123, 3383–3394 (2013). (reference 7 of Carreno et al.) for further guidance on generating mDCs.
Carreno et al. teaches using the method taught in B. M. Carreno, et al., IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity. J. Clin. Invest. 123, 3383–3394 (2013). (reference 7 of Carreno et al.) (herein referred to as Carreno et al. 2013) to generate mDCs. Carreno et al. 2013 teaches testing for CD11c and CD86 to assess mDC preparation, but does not include the results (e.g., pg. 3384, col 1; Fig. 6).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing that the method taught by Carreno et al. would result in CD11c and CD86 expression by the matured second dendritic cells being above 70%. One would be motivated for the claimed method to result in producing cells expressing CD11c and CD86 because as taught by Carreno et al. 2013, CD11c is a DC lineage marker and CD86 is a costimulatory molecule expressed by DCs (e.g., pg. 3384, col 1, “Results”; Fig. 6).
Regarding claim 2, Carreno et al. teaches inducing the dendritic cells by pulsing the dendritic cells with peptides comprising the mutated amino acid sequence or a pool of peptides (e.g., Supplementary Materials, pg. 4, “DC manufacturing and vaccine”).
Regarding claims 3-5, Carreno et al. teaches the peptides of (a) and (b) of claim 2 having a length of about 15 to 40 amino acid residues or about 8 to about 19 amino acid residues (e.g., Supplementary Materials, Table S4).
Regarding claim 9, Carreno et al. teaches sequencing the whole exosome of the cancer cell (e.g., Supplementary Materials, pg. 1-3).
Regarding claims 12 and 13, as discussed in the 112(a) rejection above, claims 11 and 12 do not recite any additional structures (e.g., active method steps). As such, absent evidence to the contrary, an Artisan would expect the method taught by Carreno et al. to result in matured dendritic cells that share the same expression profile (e.g., function/phenotype) as those produced in the claimed method.
Regarding claim 20, Carreno et al. teaches the dendritic cells being autologous to the patient (e.g., Supplementary Materials, pg. 5, “DC manufacturing and vaccine”).
Claim Rejections - 35 USC § 103
Claim(s) 1-7, 9, 12, 13, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Carreno et al. (Carreno, Beatriz M., et al. "A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells." Science 348.6236 (2015): 803-808.).
As shown above, the base claims are obvious over the base art.
Regarding claims 6 and 7, Carreno et al. does not teach (a) inducing the first dendritic cells to present the one or more mutated amino acid sequences comprises introducing nucleotide sequence(s) encoding the one or more mutated amino acid sequences into the first dendritic cells; and/or (b) inducing the second dendritic cells to present the selected one or more mutated amino acid sequences comprises introducing nucleotide sequence(s) encoding the selected one or more mutated amino acid sequences into the second dendritic cells.
However, Carreno et al. does teach transducing HLA-A*02:01+ melanoma lines DM6 or A375 with tandem mini-gene constructs (TMC). Following transduction, DM6 cells expressing TMC were co-cultured with neoantigen-specific T cells (e.g., Supplementary Materials, pg. 6, “Tandem mini-gene constructs (TMC) and antigen processing”). Additionally, peptides were purified from TMC expressing A375 melanoma cells (e.g., Supplementary Materials, pg. 7, para 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the method step of inducing cells to present an amino acid sequence by pulsing the cells with peptides taught by Carreno et al. with the method step of inducing cells to present an amino acid sequence by introducing nucleotide sequence(s), such as TMCs, also taught by Carreno et al. with a reasonable expectation for success. An artisan would have a reasonable expectation of success because the simple substitution of one known element for another (such as methods of inducing cells to present an amino acid sequence) would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re
Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).” M.P.E.P. §2144.06. One would be motivated to induce the dendritic cells by introducing a nucleotide sequence via a TMC rather than by pulsing an amino acid sequence/peptide because as taught by Carreno et al., transfecting cells with TMCs is another way to successfully evaluate neoantigen processing and presentation (e.g., pg. 805, col 2-col 3). In addition, the TMCs can comprise nucleotide sequences containing amino acid substitutions targeted by peptides included in the produced vaccine(s) (e.g., Supplementary Materials, Table S5).
Claim(s) 1-5, 9-13, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Carreno et al. as applied to claims 1-5, 9, 12, 13, and 20 above, and further in view of Karlsson-Parra et al. (US20120328662A1, published 12/27/2012).
As shown above, the base claims are anticipated by the base art, and thus, are also obvious over the base art.
Regarding claims 10 and 11, Carreno et al. teaches maturing monocyte-derived immature DCs by irradiated (10,000 rad) GMP-grade CD40L-expressing K562 cells (7), 100 u/mL IFN-γ (Actimmune, InterMune Inc.), poly I:C (Invivogen, Inc) and R848 (Invivogen, Inc.) (e.g., Supplementary Materials, pg. 4, “DC manufacturing and vaccine”). Carreno et al. does not teach maturing the DCs in the absence of CD40L-expressing K562 cells.
An artisan, interested in maturing monocyte-derived immature DCs, would be aware of Karlsson-Parra et al. for teaching methods of maturing proinflammatory DCs ex vivo.
Karlsson-Parra et al. teaches a method of producing mature DCs comprising isolating monocytes from PBMCs, generating iDCs from the monocytes, followed by inducing maturation of the iDCs by adding poly-I:C, R848 and IFN-γ to the iDCs to obtain proinflammatory mature DCs; and washing the proinflammatory mature DCs to remove substantially all stimulating factors; resulting in a substantially stimulation factor-free, proinflammatory mature DC (e.g., claim 21 of Karlsson-Parra et al.; [0070]).
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the current invention to apply the knowledge that CD40L-expressing K562 cells are not required in order to mature monocyte-derived iDCs taught by Karlsson-Parra et al. to the DC maturation step of Carreno et al. (e.g., remove CD40L-expressing K562 cells from Carreno et al.) to arrive at the claimed invention. One would have a reasonable expectation for success because Kalrsson-Parra et al. successfully matured monocyte-derived iDCs using only polyI:C and R848, or polyI:C, R848, and IFN-y (e.g., [0070]). One would be motivated to apply the teachings of Karlsson-Parra et al. because as taught by Karlsson-Parra et al., the concurrent administration intratumorally of stimulating agents (aimed to induce proinflammatory DCs ex vivo) most likely will lead to a strong and persistent activation also of intratumorally recruited immature DCs, leading to their differentiation into proinflammatory mature DCs instead of the desired differentiation into migratory mature DCs. Unfortunately, cessation of maturating stimuli like TLR4 ligands or CD40L at time points when the DCs have differentiated into mature DCs (usually after more than 12 hours of stimulation) is known to induce a rapid down-regulation of inflammatory cytokine production, including IL-12 production. Activation methods must therefore be used that activate DCs into proinflammatory mature DC with sustained production of desirable factors after cessation of the activation-inducing factors (e.g., [0050]).
Claim(s) 1-5, 8, 9, and 12-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Carreno et al. as applied to claims 1-5, 9, 12, 13, and 20 above, and further in view of Rosenberg et al. (Rosenberg, Steven A., and Nicholas P. Restifo. "Adoptive cell transfer as personalized immunotherapy for human cancer." Science 348.6230 (2015): 62-68.—published 04/03/2015).
As shown above, the base claims are anticipated by the base art, and thus, are also obvious over the base art.
Carreno et al. does not teach administering T cells to the patient.
An artisan, interested in personalized immunotherapy for cancer, would be aware of Rosenberg et al. for reviewing adoptive cell therapy (ACT) as a cancer treatment.
Rosenberg et al. teaches a “blueprint” for the treatment of patients with T cells recognizing tumor-specific mutations in Fig. 3. The treatment involves synthesizing either minigenes or polypeptides encoding each cancer-specific mutated amino acid, then expressing the peptides or minigenes in a patient’s autologous antigen-presenting cell (e.g., dendritic cells are an example of APCs). Coculture of the patient’s T cells with these APCs can be used to identify all mutations processed and presented in the context of all of a patient’s MHC class I and class II molecules. The identification of individual mutations responsible for tumor recognition is possible because T cells express activation markers, such as 41BB (CD8+ T cells) and OX40 (CD4 + T cells) (claim 8), when they recognize their cognate target antigen. T cells expressing the activation marker can then by purified using flow cytometry before their expansion and reinfusion into the tumor-bearing patient. Rosenberg notes that these approaches can be used with TILs (claim 15) (e.g., pg. 65, col 2-3).
Figure 4 of Rosenberg et al. teaches techniques to introduce antitumor receptors, such as TCR (claims 16 and 17) and CAR (claim 18), into a patient’s T cells, followed by expansion and infusion of the T cells back into the patient (e.g., also see pg. 62, col 1).
Additionally, Rosenberg et al. teaches administering immune checkpoints such as anti-PD-1 or anti-CTLA-4 to the patient (claim 19) (e.g., pg. 65, col 1, para 1).
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the current invention to combine the method(s) taught by Rosenberg et al. by adding the step(s) of administering T cells (e.g., TILs, or T cells comprising recombinant TCR, endogenous TCR, CAR, etc.) and/or an immune checkpoint inhibitor to the patient to the method taught by Carreno et al. One would have a reasonable expectation for success because Rosenberg et al. teaches co-culturing TILs, T cells with TCRs, with APCs (e.g., dendritic cells), followed by reinfusing these cells into the patient (e.g., pg. 65, Fig. 3). One would be motivated to make these modifications because as taught by Rosenberg et al., administration of immune checkpoint inhibitors such as anti-PD-I and anti-CTLA-4 and/or administration of T cells are known, successful immunotherapy approaches to treat cancer (e.g., Table 1; pg. 65, col 1, para 1).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5 and 8-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,976,299. Although the claims at issue are not identical, they are not patentably distinct from each other because the reference patient is a species of the instant application.
Claims 1, 2, 10, 11: reference claim 1 is directed to a method of inducing an immune response against one or more mutated amino acid sequences in a patient. Reference claim 1 recites the same method steps as instant claim 1. Reference claim 1 further limits inducing the dendritic cells via loading (instant claim 2), the one or more amino acid sequences being presented by a major histocompatibility complex (MHC) Class II of Class I molecule, and maturing the second dendritic cells in the presence of polyinosinic-polycytidylic acid (polyLC), resiquimod (R848), and interferon (IFN)-gamma and in the absence of a further dendritic cell stimulating agent (instant claims 10 and 11).
Claims 3-5: reference claim 2 further limits the peptides to have a length of about 15 to about 40 amino acid residues. Reference claims 3 and 4 further limit the peptides to have a length of about 8 to about 19 amino acid residues.
Claim 8: reference claim 5 further limits the T cells which are co-cultured with the first dendritic cells which present the selected one or more mutated amino acid sequences express any one or more of programmed cell death 1 (PD-1), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), 4-1BB, OX40, and CD107a.
Claim 9: reference claim 6 further limits the method to comprise sequencing the whole exome, the whole genome, or the whole transcriptome of the cancer cell.
Claim 12: reference claim 7 further limits the matured second dendritic cells to express any one or more of IL-12p70, TNFa, IP-12, MCP-1, MIP-1$, CD80, CD83, CCR7, and HLA- DR.
Claim 13: reference claim 8 further limits the matured second dendritic cells to express all of IL-12p70, TNFa, IP-12, MCP-1, MIP-1$, CD80, CD83, CCR7, and HLA-DR.
Conclusion
No claims are allowed.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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