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 .
Claims 1-12, 21-29 are under examination.
Response to Applicants Arguments/Amendments
Applicants presented convincing arguments that the prior art cited in the art rejection in the office action dated February 11, 2026 was applicants own work. As a result of the arguments presented by applicants, the former art rejection is withdrawn and new rejections put forth. The amendments have clarified the claims and the former 112(b) rejection is withdrawn. New art rejections are added.
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.
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.
Claims 1-4,6-8,11-12,21-23,25-26, and 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Kamiya (WO 2018182511) in view of Shin (US 20180355317)
Kamiya teaches co-culturing in a culture medium, a population of NK cells with a population of feeder cells for a first period of time (Paragraph 43 of Kamiya), wherein the first feeder cell population comprises cells engineered to express 4-1BBL and membrane-bound interleukin-15 (mbIL15) (Paragraphs 4-5 of Kamiya), wherein the population of NK cells comprise fewer cells than the first population of feeder cells (Paragraph 43 of Kamiya), wherein the culture medium comprises interleukin 2 (IL2) (Paragraphs 28 and 74), and wherein the co-culturing for the first period of time results in an expanded population of NK cells (Abstract). Paragraph 74 states that “every 2-3 days, fresh tissue culture medium and IL-2 can be added. Kamiya teaches that the amount of IL-2 present can be 40 IU/ml (Paragraph 74). as in instant Claims 1,3,11-12 and 21.
Furthermore, Kamiya teaches that NK cells can be expanded multiple times (Paragraph 83 of Kamiya) and the medium is changed every 2-3 days (Paragraph 74). Kamiya teaches that the NK cells are recovered and separated out after every expansion culture based on CD56 expression and lack of CD3 (Paragraph 78). MPEP 2144 B.Duplication of Parts recites the following: “In reHarza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960) (Claims at issue were directed to a water-tight masonry structure wherein a water seal of flexible material fills the joints which form between adjacent pours of concrete. The claimed water seal has a “web” which lies in the joint, and a plurality of “ribs” projecting outwardly from each side of the web into one of the adjacent concrete slabs. The prior art disclosed a flexible water stop for preventing passage of water between masses of concrete in the shape of a plus sign (+). Although the reference did not disclose a plurality of ribs, the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced.)” Therefore, it would have been obvious for a person of ordinary skill in the art to have added as many expansion steps each followed by separation steps as needed to produce the number of natural killer cells needed (100,000 fold to 5,000,000 fold expansion of NK cells) as in instant Claims 1-3,22,25,28, and 29.
Paragraph 44 of Kamiya states that the culture medium can include other interleukins that can promote the expansion of NK cells. Kamiya fails to teach including IL-12 and/or IL-18 into the culture medium used to facilitate natural killer cell expansion. However, Shin teaches that IL12 can be present in an amount of about 0.5 ng/ml to 5 µg/ml, preferably 1ng/ml to 3 ng/ml (Paragraph 64 of Shin). IL18 teaches that the cytokine solution is 2ng/ml to 50 ng/ml (Paragraph 64 of Shin). It would have been obvious to an artisan of ordinary skill at the time of effective filing to have included the additional interleukins of Shin. An artisan would have been motivated to have included IL12 and/or IL18 because they can promote the expansion of natural killer cells (Abstract and Paragraph 64 of Shin) as in instant Claims 1,3,11-12, and 21.
Dependent Claims taught by Kamiya
Further MPEP § 2144.05 (II) states, “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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“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.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int' l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”). In the instant case, neither the specification nor applicant has provided evidence that the length of time for each culture episode is critical. Therefore, Kamiya renders the claimed time for culture. Furthermore, it would be expected that a person of ordinary skill in the art would have continued to expand the population of natural killer cells produced until the desired amount (100,000-5,000,000 fold expansion occurred). Therefore, claims 3 and 22,25, and 28 are obvious.
Kamiya teaches wherein the population of NK cells is present in an amount between about 5 and about 25 times less than the population of feeder cells at inception of co-culturing (Paragraph 43) as in instant Claim 4. Kamiya teaches wherein the feeder cell population comprises K562 cells (Paragraph 8) as in instant Claim 6. Kamiya teaches wherein the co-culturing increases the cytotoxicity of the expanded NK cells and would also inherently express markers of cytotoxicity (Paragraph 57) as in instant Claims 7 and 8. Kamiya teaches wherein the population of NK cells is derived from peripheral blood (Paragraphs 24 and 28) as in instant Claims 23 and 26.
Kamiya teaches that natural killer cells can be successfully expanded on feeder cells such as K562 cells that are engineered to express 4-1BBL and mbIL15. Kamiya does not teach the culture medium that surrounds the NK cells also contains IL12 and IL18; however, Shin teaches that the culture medium can contain IL12 and IL18. An artisan would have been motivated to have included these interleukins into the culture medium because it promotes the successfully expansion of natural killer cells. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All the claimed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combinations would have yield predictable results to one of ordinary skill in the art at the time of the invention (See KSR International Col. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.s and Ph.D.s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in cell culture. Therefore, the level of ordinary skill in the art is high.
Claim 1-8,11-12,21-29 are rejected under 35 U.S.C. 103 as being unpatentable over Kamiya (WO 2018182511) in view of Shin (US 20180355317) and Kaufman (US 20130287751)
Kamiya and Shin apply as above to teach claims 1-4,6-8,11-12,21-23,25-26, and 28-29. Neither of these references teach that after each culture period, the cells undergo FACS in order to generate a nearly homogenous population of natural killer cells. However, Kaufman teaches that after an expansion stage, the population of cells containing natural killer cells undergo FACs to further purify the natural killer cells from all the other contaminating cells present (Paragraph 153 of Kaufman). It would have been obvious to an artisan of ordinary skill at the time of effective filing to have further purified the NK cells using FACs taught in Kaufman. An artisan would have been motivated to have purified the NK cells by FACs in order to generate a population that contained a greater majority of the target cells/NK cells (Paragraph 153 of Kaufman). Because FACs can successfully produce an enhanced population of NK cells, there would have been a high expectation for success (Paragraph 153 of Kaufman) as in instant Claim 5.
Kamiya uses NK cells derived from peripheral blood. Kamiya does not teach that natural killer cells can be derived from a cord blood sample. However, Kaufman teaches that natural killer cells can be derived from cord blood (Paragraph 18 of Kaufman). It would have been obvious to an artisan of ordinary skill at the time of effective filing to have used cord blood to supply natural killer cells. An artisan would have been motivated to have used cord blood to supply natural killer cells because Kaufman states that natural killer cells can be derived from cord blood (Paragraph 18 of Kaufman) as in instant Claims 24 and 27.
Kamiya teaches that natural killer cells can be successfully expanded on feeder cells such as K562 cells that are engineered to express 4-1BBL and mbIL15. Kamiya does not teach the culture medium that surrounds the NK cells also contains IL12 and IL18; however, Shin teaches that the culture medium can contain IL12 and IL18. An artisan would have been motivated to have included these interleukins into the culture medium because it promotes the successfully expansion of natural killer cells.
Kamiya does not teach purification after each round of culture using FACs; however, Kaufman teaches that such a process is desirable because it better purifies the population of NK cells. Kamiya harvests the NK cells from only peripheral blood; however, it would have also been obvious to have harvested NK cells from cord blood since Kaufman teaches that natural killer cells can be successfully derived from cord blood. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All the claimed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combinations would have yield predictable results to one of ordinary skill in the art at the time of the invention (See KSR International Col. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.s and Ph.D.s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in cell culture. Therefore, the level of ordinary skill in the art is high.
Claims 1-4,6-12,21-23,25-26, and 28-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kamiya (WO 2018182511) in view of Shin (US 20180355317) and Lan (US 20180221463)
Kamiya and Shin apply as above to teach claims 1-4,6-8,11-12,21-23,25-26, and 28-29. Kamiya does not teach that the natural killer cells are modified to express a chimeric antigen receptor that is able to target tumor antigen CD19; however, Lan teaches that the natural killer cells can be genetically modified to express a chimeric antigen receptor that is able to bind to CD19 which is a tumor antigen (Paragraph 67 of Lan). It would have been obvious to an artisan of ordinary skill at the time of effective filing to have used the genetic modification taught by Lan. An artisan would have been motivated to have used the genetic modification taught by Lan because it can target cancer/tumor antigens that express CD19 (Paragraph 67). Because CAR modified NK cells can attack cancer cells, there would have been a high expectation for success (Paragraph 67) as in instant Claims 9-10.
Kamiya teaches that natural killer cells can be successfully expanded on feeder cells such as K562 cells that are engineered to express 4-1BBL and mbIL15. Kamiya does not teach the culture medium that surrounds the NK cells also contains IL12 and IL18; however, Shin teaches that the culture medium can contain IL12 and IL18. An artisan would have been motivated to have included these interleukins into the culture medium because it promotes the successfully expansion of natural killer cells. Given the teachings of the cited references and the level of skill of an ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All the claimed elements were known in the prior art, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combinations would have yield predictable results to one of ordinary skill in the art at the time of the invention (See KSR International Col. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.s and Ph.D.s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in cell culture. Therefore, the level of ordinary skill in the art is high.
Conclusion
All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN K VAN BUREN whose telephone number is (571)270-1025. The examiner can normally be reached M-F:9:30am-5:40pm; 9:00-10:00pm.
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LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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