DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 1-13 as preliminarily amended on 12/29/2023 are currently pending and under consideration on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 1-3, 6, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Henco et al. (WO 2014/106631; provided in the IDS dated 12/29/2023).
Henco teaches a method of inducing monocytes to differentiate into dendritic cells, the method comprising obtaining a blood sample (e.g. comprising peripheral blood mononuclear cells) and subjecting the monocytes in the obtained blood sample to a shear force range of about 0.1-10.0 dynes/cm2 such that the monocytes bind to activated platelets(claims 1, 14, and 46), reading in-part on claim 1, the embodiment of dendritic cells for claims 2 and 6, and the embodiment of activated platelets for the generic activating agent of claim 3. In a separate embodiment, Henco teaches that activated platelets need about 60-120 minutes to express factors such as P-selectin which then activate monocytes (p50, lines 5-17), reading in-part on claim 1. In a separate embodiment, Henco teaches culturing the monocytes (p65, lines 15-28), reading in-part on claim 1. Henco teaches further stimulating the monocyte-derived dendritic cells with LPS (p81, line 19 through p83, line 3), reading on claim 7.
Regarding claim 1, Henco does not teach application of a fluid shear stress from 0.5-20 dynes/cm2, a time range of 5-120 minutes, and culturing the dendritic cells in the same embodiment. However, It would have been obvious to a person of ordinary skill in the art before the invention was filed to combine the separate application of a fluid shear stress from 0.5-20 dynes/cm2, a time range of 5-120 minutes, and culturing into a single embodiment in view of Henco’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so and the skilled artisan would have been motivated to do so because Henco expressly teaches that the combination of shear force(s) and activated platelets differentiates the monocytes into dendritic cells, and that a time range of 60-120 minutes would be desirable to give the activated platelets sufficient time to express factors such as P-selectin which then activate monocytes and because Henco expressly contemplates an additional cell culturing step.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Henco applied to claims 1 and 3 above, and further in view of Li et al. (The Journal of Immunology (2010), 184, 5959-5963; Reference U) and Blackstone et al. (US 2008/0131445; Reference A).
The teachings of Henco are relied upon as set forth above. Henco envisions treating subjects suffering from autoimmune disease(s) with the autologous immunosuppressive dendritic cells (p5, lines 12-15), reading in-part on claims 4 and 5.
Regarding claim 4, Henco does not teach T cell(s). Regarding claim 5, Henco and Li do not teach any species of anti-CD3 and anti-CD28 antibody.
Li teaches that a mild perpendicular shear stress mechanically activates T cells by inducing a calcium response (the paragraph spanning both columns on p5961, and Fig. 2), reading on claim 4.
Blackstone teaches administering immunosuppressive T cells to subjects to modulate an autoimmune reaction (¶0129), reading on claim 4. Blackstone teaches expanding the T cells in vitro with the combination of an anti-CD3 and anti-CD28 antibody (¶0073), reading on claim 5.
Regarding claims 4 and 5, it would have been obvious to a person of ordinary skill in the art before the invention was filed to further generate T cells in the methods of Henco in view of Li and in view of and with the anti-CD3 and anti-CD28 antibodies of Blackstone. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Henco and Li are in-part directed towards white blood cell compositions and activation of said white blood cells, because both Henco and Blackstone are directed in-part towards treating subjects for autoimmune disease(s), and because Li teaches there is a known association between mechanical shear stress and T cell activation. The skilled artisan would have been motivated to do so because Blackstone teaches that a subset of T cells, immunosuppressive T cells, would be advantageous to treat subjects suffering from autoimmune disease, and so Henco’s methods would then predictably and advantageously generate T cells for the downstream use of treating autoimmune disease envisioned by Henco and as also taught by Blackstone.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Henco as applied to claims 1 and 3 above, and further in view of Nickerson et al. (US 2013/0344501; Reference B).
The teachings of Henco are relied upon as set forth above.
Regarding claim 4, Henco does not teach natural killer cell(s).
Nickerson teaches methods of culturing a plurality of immune cells under low fluid shear (stress) conditions to generate a three-dimensional, physiologically relevant immune tissue system (Abstract, and ¶0086), reading on claim 5. Nickerson teaches a low fluid shear condition range from about 0-10.0 dynes/cm2 or about 0.1-1.9 dynes/cm2 (¶0079 and ¶0100), reading on claim 5. Nickerson teaches immune cells comprising dendritic cells and natural killer cells (¶0011), reading on claim 8.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to add the natural killer cells of Nickerson to the methods and activated dendritic cells of Henco A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Henco and Nickerson are in-part directed towards immune cell compositions and methods of culturing thereof and are both directed to coextensive shear stress ranges. The skilled artisan would have been motivated to do so because Nickerson teaches that the combination of multiple types of immune cells would be predictably advantageous to generate a three-dimensional, physiologically relevant immune tissue system and thus improve upon the methods of Henco.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Henco and Nickerson as applied to claims 1, 3, and 8 above, and further in view of Henney et al. (Nature (1981), 291, 335-338; Reference V).
The teachings of Henco and Nickerson are relied upon as set forth above.
Regarding claim 9, Henco and Nickerson do not teach activating natural killer cell(s) with interleukin-2 (IL-2).
Henney teaches that interleukin-2 enhances the cytotoxic activity of natural killer cells (see the bolded Abstract on p355), reading on claim 9. Henney teaches that there was a need in this art at that time to augment natural killer cell reactivity both in vivo and in vitro (p337, right column, paragraph starting “There has been much recent interest…”), reading on claim 9.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to further add the IL-2 of Henney to the methods of Henco in view of Nickerson. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Henco, Nickerson, and Henney are in-part directed towards immune cell compositions and methods of culturing thereof. The skilled artisan would have been motivated to do so because the addition of IL-2 to the natural killer cells of Nickerson in Henco’s methods would predictably enhance the cytotoxic activity of the natural killer cells.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Henco as applied to claim 1 above, and further in view of Kozbial (US 10,647,954; Reference C).
The teachings of Henco are relied upon as set forth above. Henco further teaches varying the flow rate by controlling the speed of the pump (the paragraph spanning p51-52), reading in-part on claim 10.
Regarding claim 10, Henco does not teach a closed loop peristaltic pump.
Kozbial teaches an automated cell culture cartridge for generating dendritic cells (Abstract and Col. 1, line 59 through Col. 2, line 3). Kozbial teaches a cell culture system comprising a peristaltic pump for continuous perfusion of fresh (culture) medium (Fig. 6,Col. 3, lines 14-21, and Col. 10, lines 47-50), reading on claim 10. Kozbial teaches that the cell culture system is a closed tubing system (Col. 24, lines 29-38), reading on claim 10. Kozbial teaches that their cell culture system is advantageous to produce dendritic cells on a clinical scale (Col. 2, line 65 through Col. 3, line 21), reading on claim 10.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the pump and cell culture system of Henco with the peristaltic pump and closed system of Kozbial in Henco’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Henco and Kozbial are directed towards pump-driven cell culture systems and methods of generating dendritic cells The skilled artisan would have been motivated to do so because Kozbial teaches that their automated and closed cell culture cartridge for generating dendritic cells and comprising a peristaltic pump is predictably advantageous to generate dendritic cells on a clinical scale, and so would improve upon the methods of generating dendritic cells of Henco.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Henco as applied to claim 1 above, and further in view of Lühr et al. (Frontiers in Immunology (Nov. 2020), 11, Article 590121; Reference W) and Sawyer et al. (US 2019/0270962; Reference D).
The teachings of Henco are relied upon as set forth above.
Regarding claim 11, Henco does not teach adding any species of additive to provide a viscosity of 0.01-6.0 poise (being equivalent 0.001-0.6 Pa . s).
Lühr teaches methods of making and culturing monocyte-derived dendritic cells (the paragraph spanning p3-4) Lühr teaches adding 0.5% methylcellulose to change the viscosity of the cells suspended in PBS (p4, paragraph starting “Real-time fluorescence…), reading in-part on claim 11.
Sawyer teaches a system for monitoring and screening animal cells in culture (Abstract and ¶0070). Sawyer teaches depositing the cells in a growth medium possessing a yield stress material (¶0046), wherein the yield stress material possessing a viscosity range of approximately 0.1-10,000 Pa . s or 0.1-10 Pa . s (i.e. equating to approximately 1-100,000 poise or 1-100 poise respectively; see ¶0049 and ¶0061), reading on claim 11. Sawyer teaches methods of screening therapeutic agents against immune cells (¶0028 and ¶0032), reading on claim 11
It would have been obvious to a person of ordinary skill in the art before the invention was filed to add the methylcellulose of Lühr to yield the viscosity ranges of Sawyer in the methods of Henco. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Henco and Lühr are in-part directed towards methods of making and culturing monocyte-derived dendritic cells, and because Henco, Lühr, an Sawyer are all in-part directed towards methods of culturing animal cells. The skilled artisan would have been motivated to do so because Sawyer teaches that a cell culture medium possessing a viscosity range of approximately 0.1-10,000 Pa . s or 0.1-10 Pa . s (i.e. equating to approximately 1-100,000 poise or 1-100 poise respectively) would be useful in methods of screening therapeutic agents against immune cells, and thus improving upon the cell culture medium of Henco.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Henco, Lühr, and Sawyer as applied to claims 1 and 11 above, and further in view of Michaels (Biotechnology and Bioengineering (1995), 47, 420-430; Reference X).
The teachings of Henco are relied upon as set forth above.
Regarding claim 12, Henco, Lühr, and Sawyer do not teach adding Pluronic F68 and/or polyethylene glycol (i.e. PEG).
Michaels teaches adding Pluronic F68 and/or polyethylene glycol to culture medium compositions to modify the viscosities of said compositions and protect mammalian cells against shear damage (Abstract).
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the Pluronic F68 and/or polyethylene glycol of Michaels for the methylcellulose of Lühr added to Henco’s methods in view of Sawyer because Pluronic F68, polyethylene glycol, and methylcellulose are all explicitly taught as being useful for THE SAME PURPOSE of modifying the viscosity of aqueous compositions comprising cells. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Henco as applied to claim 1 above, and further in view of Chakraborty et al. (Cell Reports (Jan. 2021), 34, 108609; Reference U2).
The teachings of Henco are relied upon as set forth above.
Regarding claim 13, Henco does not teach assaying the embodiment of monocyte-derived dendritic cells for Piezo1 expression and then further selecting a fluid shear stress, viscosity, time, or any combination thereof based on the Piezo1 expression levels.
Chakraborty teaches that Piezo1 is a Ca2+-dependent mechanosensitive (ion) channel and Peizo1 agonism upregulates the production of IL-6 and TNF-α in bone marrow-derived dendritic cells (BMDCs) cultured in vitro and that Piezo1 deficiency in mice reduces the dendritic cell (DC)-mediated anti-tumor response (the paragraph spanning both columns on p9, and Fig. 5G, 5H, and 5L), reading in-part on claim 13.
Regarding claim 13, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, Henco teaches that the fluid shear stress and the time range to apply said fluid shear stress are effective to generate monocyte-derived dendritic cells, and Chakraborty teaches there is a known association between Piezo1 and dendritic cell function. Thus, any further selection a fluid shear stress, viscosity, time, or any combination thereof based on the Piezo1 expression levels must be held as routine optimization over Henco in view of Chakraborty, in the absence of any evidence of nonobviousness to the contrary.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Conclusion
No claims are allowed. No claims are free of the art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653