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 .
DETAILED ACTION
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-2, 4-7, and 9-14 have an effective filing date of 04SEP2019.
Status of Claims
Claims 1-2, 4-7, and 9-14 are currently pending and presented for examination on the merits.
Claims 3, 8, and 15-24 are canceled.
Rejections Withdrawn
The rejection filed under 35 U.S.C. 112(b) are withdrawn in view of Applicant’s amendment to claims.
New Rejections
Claim Rejections - 35 USC § 112
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 1-2, 4-7, and 9-14 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, lines 6-8, recite the limitation of “do not comprise, an exogenous gene, an exogenous transcript, an exogenous protein, an exogenous nuclear component or cytoplasm, or cell fusion.”. It is unclear if Applicant means one or none of items are not to be comprised on the de-differentiated non-adherent cancer cells. Clarification is required.
Rejection Maintained
Claim Rejections - 35 USC § 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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The 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.
Claims 1-2, 4-7, 9-14 are rejected under 35 U.S.C. 103 as being unpatentable over Emens (Cancer Vaccines: on the threshold of success, Expert Opin Emerg Drugs. 2008 June; 13(2): 295–308), Vacanti et al (WO 2015143125, IDS 9/7/2021), Chiang et al (Whole Tumor Antigen Vaccines, Semin Immunol. 2010 June ; 22(3): 132–143) , and further in view of Kalantarov et al (WO 2017152008 A1).
Emens teaches the use of tumor cell vaccines [Section 5.6, pg. 8]. Emens further teaches the advantage of whole tumor cell vaccines (i.e. inclusive of differentiated cells with a diverse panel of tumor antigens, both known and unknown, which provides CD8+ and CD4+ T-cell epitopes) is that it delivers a diverse panel of tumor antigens [Section 5.6, pg. 8]. Emens further teaches tumor cells are not inherently immunogenic, they are modified with adjuvants such as BCG [Section 5.6, pg. 8]. Emens further teaches the vaccines can use either autologous tumor cells or allogenic tumor cells [Section 5.6, pg. 8]. Emens further teaches the whole tumor cells deliver antigens that prime the subjects antitumor immune response [Section 5.6, pg. 8]. Emens further teaches vaccine using whole tumor cells or tumor cell lysate [2nd Paragraph, pg. 3]. Emens further teaches cancer cell vaccine administered in renal cell carcinomas and melanoma [Section 6.4 Tumor cell vaccines, pg. 10].
Emens does not specifically teach a cancer vaccine comprising stress reprogrammed de-differentiated cancer cells, the benefits of using dedifferentiated cells, pluripotent cells that are non-adherent, de-differentiate cells by damaging them by mechanical injury, and exposing cells to a pH between 3.5 and about 5.8, and cells in sphere media. However, this deficiency is made up in the teachings Vacanti et al.
Vacanti et al teaches the production or generation of pluripotent cells from differentiated cells [0035]. Applicant states in the Specifications that inducing stress to a cell by reducing the cytoplasm or mitochondria, triggers a dedifferentiation process and results in pluripotent cells [Applicant SPEC, line 3, pg. 20]. The broadest reasonable interpretation is that a mature cell that reverts to a pluripotent cell is a dedifferentiated cell, and the resulting pluripotent cells would express the markers of pluripotency not expressed on the differentiated cancer cells. Vacanti et al further teaches that stress can induce the production of pluripotent stem cells from cells [0035]. Vacanti disclose that the pluripotent cell can be derived from a cancer cell [0096]. Vacanti et al further teaches cells exposed to the stressing agent have a pH between 4.0 to 6.8 [0216, & Figure 5B]. Vacanti et al further teaches that cells can be exposed to ATP to induce generation of pluripotent cells [0082]. Vacanti et al further teaches chemical injury stress to cell to induce stem cells [00208]. Vacanti et al further teaches chemical stress by exposing cells to low pH [00208]. Vacanti et al further teaches to induce stem cells using agitation or trituration [00177 and 00178]. Vacanti et al further teaches using both chemical and mechanical injury to cells [00216]. Vacanti et al further teaches mechanical agitation by pipette [0079]. Vacanti et al further teaches the use of sphere media to maintain cells in [0174]. Vacanti et al further teaches centrifuging at about 800 -1600 rpm for 1-20 minutes [0159]. Vacanti et al further teaches to make a cancer vaccine with a diverse and changing antigen profile [0114]. Vacanti et al further teaches pluripotent cells (i.e. de-differentiated cancer cells) expressing antigens not expressed on mature cells [0249 & 0098]. Vacanti et al further teaches administering the cells subcutaneously [0131]. Vacanti et al further teaches the benefit of using dedifferentiated cells is to provide markers not present on the cells in tissue [0036]. Vacanti et al further teaches the benefits of reverted pluripotent cells (dedifferentiated cells) is that pluripotent cells can fuse with non-pluripotent cells, mature cells, malignant cells, and/or damaged cells, and increase their health by increasing repair of cellular damage, mutations, and/or modifications of the epigenetic status of the recipient cell [0139]. Vacanti et al further teaches by increasing a cell’s pluripotency in vivo the epigenetic markers can be modulated and treat epigenetically-linked conditions such as malignancy, arthritis, autoimmune disease, and aging [0140]. Vacanti et al further teaches the ability to select pluripotent cells by their inability to adhere [0094]. Vacanti et al further teaches stresses to de-differentiate cells such as ultrasonic stimulation [0088].
Emens does not specifically teach a motivation to use a population of differentiated cancer cells and de-differentiated cancer cells, and obtaining cancer cells from a single patient or multiple individuals. However, this deficiency is made up in Chiang et al.
Chiang et al teaches whole cell tumor vaccines [Abstract, pg. 1]. Chiang et al further teaches tumor associated antigens (TAA) [Introduction, pg. 1]. Chiang et al further teaches five categories of TAAs: mutated antigens expressed uniquely by tumors, overexpressed antigens, oncofetal antigens, differentiation antigens, and cancer-testis antigens [Introduction, pgs. 1-2]. Chiang et al further teaches live whole tumor cells are poorly immunogenic due to the cells secreting soluble factors that inhibit immune cell mediated killing of the tumor cells [1st Paragraph, pg. 4]. Chiang et al further teaches administering a cancer vaccine subcutaneously [1st Paragraph, pg. 7]. Chiang et al further teaches increasing immunogenicity of whole-cell cancer vaccine by administering a potent adjuvant [1st Paragraph, pg. 5]. Chiang et al further teaches autologous, collected from a single patient, or allogeneic and obtained from multiple patients [Last paragraph, pg. 2]. Chiang et al further teaches the benefit of allogeneic cancer cells is that they provide a shared or even several of the tumor associated antigens and a simpler method of delivering antigens [Last paragraph, pg. 2].
Emens et al does not specifically teach attenuated or killed cells to make a cancer vaccine. However, this deficiency is made up in the teaches of Kalantarov et al.
Kalantarov et al teaches a method of making a cancer vaccine [0030]. Kalantarov et al further teaches using either killed or attenuated cancer cells [0030]. Kalantarov et al further teaches the benefit of using killed or attenuated cancer cells to treat cancer in a subject is they elicit a strong immune response against the identified cancer in the subject [0030].
With regard to the cells are exposed to a pH between 3.5 and about 5.8, the pH needed to de-differentiate cancer cells is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount pH to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of pH would have been obvious at the time of applicant's invention. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
One of ordinary skill, before the effective filing date would have been motivated to combine Emens’s tumor cell vaccine comprising autologous or allogenic tumor cells or lysate which contain differentiated cancer cells expressing TAAs, with Vacanti’s method of stress reprogramming de-differentiating mature cells into cells that express markers of pluripotency that are not expressed on the mature cells, with Chiang’s method of targeting an array of TAA to include differentiated and stem cells, with Kalantarov’s method of making a cancer vaccine using attenuated or killed cancer cells. The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143.
It would have been prima facie obvious to combine Emens, Vacanti, Chiang, and Kalantarov’s teachings for a cancer vaccine comprising differentiated cells expressing cancer antigens and stress reprogrammed attenuated de-differentiated non-adherent cancer cells induced to express markers associated with pluripotency and not expressed on mature cancer cells, because Chiang teaches identifying these TAAs as targets for a cancer vaccine, Emens teaches the benefits of having diverse TAAs to better kill tumor cells, Vacanti teaches the benefits of a diverse set of antigens for the development of more powerful APB (antigen presenting cell)-based cancer vaccines, and Kalantarov teaches attenuated cancer cells elicit a strong immune response.
Applicant’s Arguments:
Applicant respectfully traverses
The claimed cancer vaccines exploit Applicant's findings that non-stem cancer cells obtained from a subject with cancer can be induced to express markers associated with pluripotency and cancer cell antigens not present on differentiated cancer cells by exposure to one or more environmental non-lethal stresses, providing a plethora of stem and non-stem cancer antigens that are not described in the art.
Emens does not teach or suggest cancer cells that express markers associated with pluripotency and cancer cell antigens not present on differentiated cancer cells as required by the claims.
Vacanti does not cure the deficiencies of Emens, at least because Vacanti does not teach or suggest inducing or enhancing innate immune responses, nor does Vacanti teach or suggest T cell immunity at all.
Chiang does not teach or suggest that it was even possible to de-differentiate cancer cells by stress-treatment for any purpose, much less that these de-differentiated cancer cells could be useful for a cancer vaccine.
The claimed vaccines are formulated from cancer cells that are induced to express markers of pluripotency by exposure of mature, differentiated cancer cells to sub-lethal stressors. The compositions and methods that required specific systems to kill tumor cells of Chiang are therefore non-compatible with the claimed vaccines that require stress de- differentiated cancer cells and differentiated cancer cells.
Kalantarov does not teach or suggest a cancer vaccine comprising stress reprogrammed dedifferentiated cancer cells. Kalantarov does not teach or suggest cancer cells that express markers associated with pluripotency and cancer cell antigens not present on differentiated cancer cells.
Examiner’s Response:
One of ordinary skill in the art, before the effective filing date would have been motivated to combine Emens’s method of producing a cancer vaccine comprising autologous or allogenic tumor cells or lysate which contain differentiated cancer cells’ expressing TAAs, with Vacanti’s method of stress reprogramming de-differentiating mature cells into cells that express markers of pluripotency that are not expressed on the mature cells, with Chiang’s method of targeting an array of TAA to include differentiated and stem cells, with Kalantarov’s method of making a cancer vaccine using attenuated or killed cancer cells, because Emens teaches methods of producing a cancer vaccine comprising cancer cells, Vacanti teaches educing cancer cells to de-differentiate and express antigens not present on mature cells, Chiang teaches identifying target antigens for a cancer vaccine, and Kalantarov teaches attenuated cancer cells elicit a strong immune response.
Applicant states, “Emens does not teach or suggest cancer cells that express markers associated with pluripotency and cancer cell antigens not present on differentiated cancer cells as required by the claims.”
This deficiency is taught by Vacanti et al teaches that stress can induce the production of pluripotent stem cells from cells [0035]. Vacanti disclose that the pluripotent cell can be derived from a cancer cell [0096]. Vacanti et al further teaches pluripotent cells (i.e. de-differentiated cancer cells) expressing antigens not expressed on mature cells [0249 & 0098]. Vacanti et al further teaches by increasing cell’s pluripotency in vivo the epigenetic markers can be modulated and treat epigenetically-linked conditions such as malignancy, arthritis, autoimmune disease, and aging [0140].
Applicant states, “Vacanti does not teach or suggest inducing or enhancing innate immune responses, nor does Vacanti teach or suggest T cell immunity at all.”
These limitations are not present in the claims. The claims are directed to a cancer vaccine.
Applicant states, “Chiang does not teach or suggest that it was even possible to de-differentiate cancer cells by stress-treatment for any purpose, much less that these de-differentiated cancer cells could be useful for a cancer vaccine.”, and “The claimed vaccines are formulated from cancer cells that are induced to express markers of pluripotency by exposure of mature, differentiated cancer cells to sub-lethal stressors.”.
This deficiency is made up in the teaches of Vacanti et al teaches that stress can induce the production of pluripotent stem cells from cells [0035]. Vacanti disclose that the pluripotent cell can be derived from a cancer cell [0096]. Vacanti et al further teaches pluripotent cells (i.e. de-differentiated cancer cells) expressing antigens not expressed on mature cells [0249 & 0098]. Vacanti et al further teaches by increasing cell’s pluripotency in vivo the epigenetic markers can be modulated and treat epigenetically-linked conditions such as malignancy, arthritis, autoimmune disease, and aging [0140].
Applicant states, “Kalantarov does not teach or suggest a cancer vaccine comprising stress reprogrammed dedifferentiated cancer cells. Kalantarov does not teach or suggest cancer cells that express markers associated with pluripotency and cancer cell antigens not present on differentiated cancer cells.”
This deficiency is made up in the teaches of Vacanti et al teaches that stress can induce the production of pluripotent stem cells from cells [0035]. Vacanti disclose that the pluripotent cell can be derived from a cancer cell [0096]. Vacanti et al further teaches pluripotent cells (i.e. de-differentiated cancer cells) expressing antigens not expressed on mature cells [0249 & 0098]. Vacanti et al further teaches by increasing a cell’s pluripotency in vivo the epigenetic markers can be modulated and treat epigenetically-linked conditions such as malignancy, arthritis, autoimmune disease, and aging [0140].
Although Ebens et al. teach that some tumor cell vaccines are ineffective in treating cancer, based upon the teachings of the prior art, as a whole, one of ordinary skill in the art would have had ample motivation to combine the cited references to arrive at the claimed invention, because there would have been a reasonable expectation that the invention of the prior art is effective in the treatment of cancer.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS JOHN SULLIVAN whose telephone number is (571)272-0509. The examiner can normally be reached Mon - Fri: 7:30AM - 4:30PM.
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/DENNIS J SULLIVAN/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642