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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06 August 2025 has been entered.
Status of the Claims
Applicant’s submission filed 06 August 2025 has been entered. Claims 1-2, 4, 6-8, 10, 12, 14, 17, 23-24, 29-30, 32-34, 37, 40, and 86 are pending. Claims 1 and 30 have been amended, with support for the amendments found in Paragraph [0041] of the instant Specification. Therefore, prosecution on the merits continues for claims 1-2, 4, 7-8, 10, 12, 14, 17, 23-24, 29-30, 32-34, 37, 40, and 86 for being drawn to the elected invention and species, with claim 6 withdrawn for reading on the non-elected species. All arguments have been fully considered with the status of each prior ground of rejection set forth below.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1-2, 4, 7-8, 10, 12, 14, 17, 23, 32-34, 37, 40, and 86 under 35 USC 103 over Berenson et al in view of Kaiser et al
Applicant has amended independent claim 1, necessitating the antibody-coated microparticle within the activation method to have a stiffness between 10 kPa and 30 kPa. As this limitation was recited in previous claim 30, which was not included within the rejection of record, the rejection of record is obviated.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1-2, 4, 7-8, 10, 12, 14, 17, 23-24, 29, 32-34, 37, 40, and 86 under 35 USC 103 over Berenson et al in view of Kaiser et al and Trickett et al
Applicant has amended independent claim 1, necessitating the antibody-coated microparticle within the activation method to have a stiffness between 10 kPa and 30 kPa. As this limitation was recited in previous claim 30, which was not included within the rejection of record, the rejection of record is obviated.
Therefore, the rejection is withdrawn.
RE: Rejection of claims 1-2, 4, 7-8, 10, 12, 14, 17, 23, 30, 32-34, 37, 40, and 86 under 35 USC 103 over Berenson et al in view of Kaiser et al and Wahl et al
Applicant's arguments filed 06 August 2025 have been fully considered but they are not persuasive.
Applicant has traversed the rejection, asserting in Pages 6-7 of the Remarks filed 06 August 2025 that Berenson et al provide no experimental evidence that PDMS beads can be used to activate immune cells. In response, the Examiner respectfully submits that prior art is not required to reduce to practice or demonstrate efficacy of the claimed invention, so long as one skilled in the art will be able to practice it without an undue amount of experimentation. See MPEP § 2121(III) and 2164.02. In the instant case, the disclosure of Berenson et al teaches the activation of T cells with antibody-coated polymeric beads , including antibody-coated PDMS beads (Paragraphs [0011], [0014], [0065], [0068], [0077], [0137]). It would not have been outside the skillset of the ordinary artisan, nor cause undue experimentation, to fabricate antibody-coated beads from various polymers.
Applicant has further traversed the rejection, asserting in Page 8 of the Remarks filed 06 August 2025 that Wahl et al disclose the use of a planar PDMS substrate and not a PDMS bead. In response, the Examiner respectfully submits that the ordinary artisan would recognize from the disclosure of Wahl et al that the stiffness of the PDMS, not the orientation, impact the spreading of the T cells. See Page 5909 of Wahl et al, wherein Wahl et al disclose that the data are solely dependent upon the stiffness of the substrate and not the chemical structure of the substrate. Therefore, so long as the PDMS bead has a stiffness of 20 kPa, the effects will be the same as indicated by the planar PDMS having a stiffness of 20 kPa.
Applicant has further traversed the rejection, asserting in Pages 8-9 of the Remarks filed 06 August 2025 that the instant disclosure unexpectedly discovered that T cells cultured in oscillating conditions with 4.5 μm microparticles having a high density of stimulatory antibodies had a greater expansion than T cells cultured in static conditions with Dynabeads. Applicant then concludes that the ordinary artisan would not have recognized that softer antibody-coated microparticles provide better activation than static Dynabeads from the disclosure of Berenson et al, as Berenson et al only use Dynabeads within the working examples. In response, the Examiner respectfully submits that, in submitting evidence asserted to establish unobvious results, there is a burden on Applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter relative to the prior art subject matter MPEP § 2145. It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. MPEP § 716.02(b). In the instant case, the closest prior art of Berenson et al is not represented by the static culture of T cells with Dynabeads; instead, Berenson et al disclose working examples wherein T cells are cultured with Dynabeads under oscillating conditions. See, for example, Paragraphs [0286]-[0287] of Berenson et al. In addition, the Examiner respectfully notes that the purported unexpected results are not commensurate in scope with the subject matter of the instant claims, as the purported unexpected results utilize alginate microparticles having a stiffness of 14.6 kPa, a diameter of 4.5 μm, and are coated with a high density of stimulatory antibodies. Therefore, these utilized alginate microparticles have a much narrower scope than the instantly claimed “antibody-coated microparticle having a stiffness between 10 kPa and 30 kPa”, as recited in instant claim 1.
Applicant has lastly traversed the rejection, asserting in Pages 9-10 of the Remarks filed 06 August 2025 that the ordinary artisan would not have arrived at the microparticle stiffness of 20 kPa without the use of hindsight reasoning. In response, the Examiner respectfully submits that it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, the ordinary artisan would have been motivated to utilize PDMS having a stiffness of 20 kPa since Wahl et al suggest that T cell activation is increased when the T cells are in contact with substrates stiffer than a few kPa. See Page 5912 of Wahl et al. Therefore, the ordinary artisan would have been motivated to utilize PDMS substrates that have a stiffness greater than a few kPa, yet still fall within the optimal T cell spreading substrate stiffness, which includes 20 kPa.
Consequently, the rejection is maintained and amended to encompass the claims as currently written.
New/Maintained Grounds of Rejection
Claims 1-2, 4, 7-8, 10, 12, 14, 17, 23, 30, 32-34, 37, 40, and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson et al (US 2003/0119185 A1, of record) in view of Kaiser et al (US 2017/0037370 A1, of record) and Wahl et al (PNAS, 2019, of record).
Berenson et al and Kaiser et al are each considered prior art under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2). Wahl et al is considered prior art under 35 U.S.C. 102(a)(1).
Regarding claims 1-2, 4, 17, and 86: Berenson et al disclose methods for activating and expanding a population of T cells by cell surface moiety ligation, comprising: a) providing a population of cells wherein at least a portion thereof comprises T cells; b) contacting said population of cells with a surface, wherein said surface has attached thereto one or more agents that ligate a cell surface moiety of at least a portion of the T cells and stimulates said T cells (Abstract; Paragraphs [0011], [0014], [0068]). Berenson et al further disclose that the surface is a microparticle or paramagnetic bead, and that the agents attached to the surface include anti-CD3 and anti-CD28 antibodies (Paragraphs [0014], [0019], [0065], [0077]). Berenson et al further disclose that the surface – or beads – may be comprised of polymers, including polydimethylsiloxane (PDMS) (Paragraph [0137]). It is of note that Berenson et al further disclose that the T cells are CD4+ or CD8+ regulatory T cells obtained from a subject blood sample (Paragraphs [0053], [0071]-[0072], [0090]-[0091], [0116]).
Berenson et al further disclose that the contacted T cells are subject to external stimulation via a rocker or other form of agitation (Paragraphs [0013], [0106]-[0107], [0126]).
Berenson et al do not disclose wherein the rocker or other form of agitation is provided at a speed between 150 rotations per minute (rpm) and 500 rpm, nor that the antibody-coated beads have a stiffness from 10 kPa to 30 kPa, as required by instant claim 1.
Kaiser et al, however, disclose a process for generating genetically modified T cells, wherein the T cells are contacted with anti-CD3/anti-CD28 beads and subject to rotation at 300 rpm (Abstract; Paragraphs [0018]-[0028], [0034], [0058]).
Therefore, it would have been prima facie obvious to modify the T cell activation method of Berenson et al to instead utilize an agitation step that is provided at 300 rpm as detailed in Kaiser et al, as doing so would a simple substitution of one known T cell activation mixing step for another. See MPEP § 2143(I)(B). One of ordinary skill in the art before the effective filing date of the invention would have been able to substitute these mixing steps and still yield predictable results, as both Berenson et al and Kaiser et al are concerned with the activation of T cells via the use of anti-CD3/anti-CD28 beads.
Berenson et al as modified by Kaiser et al still do not teach the stiffness of the antibody-coated beads, wherein the stiffness is between 10 kPa and 30 kPa.
Wahl et al, however, disclose the culturing of T cells with PDMS functionalized with anti-CD3 and anti-CD28 antibodies (Page 5909, Column 1). Wahl et al further disclose that the functionalized PDMS has a stiffness of 20 kPa (Figures 1, 3).
Therefore, it would have been prima facie obvious to modify the anti-CD3/anti-CD28 PDMS beads of Berenson et al such that the stiffness of the beads is 20 kPa, as detailed in Wahl et al. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to have anti-CD3/anti-CD28 beads that allow for maximal spreading of T cells due to the substrate stiffness (Wahl et al: Figures 1, 3), and would have had a reasonable expectation of success since the disclosures of Berenson et al, Kaiser et al, and Wahl et al all concern the culture of T cells with anti-CD3/anti-CD28 substrates. See MPEP § 2143(I)(G).
Consequently, Berenson et al as modified by Kaiser et al and Wahl et al render obvious a method wherein CD4+ or CD8+ regulatory T cells (claims 17 and 86) obtained and isolated from a subject blood sample (claims 2 and 4) are mixed with anti-CD3/anti-CD28 antibody-coated PDMS beads having a stiffness of 20 kPa, which are then subjected to an external oscillatory agitation a speed of 300 rpm. As 20 kPa and 300 rpm are specific examples within the claimed ranges, this therefore renders obvious the method of the instant claim 1. See MPEP § 2131.03(I).
Regarding claims 7 and 10: Following the discussion of claim 1, Berenson et al further disclose that the activated T cells are administered back to the subject in an autologous cell therapy (claim 10) (Paragraph [0170], [0178]-[0179]). This therefore reads on the method of instant claim 7.
Regarding claim 8: Following the discussion of claim 7, Berenson et al further disclose that the subject may additionally be administered traditional cancer therapies, vaccines, cytokines, or therapeutic antibodies (Paragraphs [0173], [0180]). As the administration of at least cytokines and/or therapeutic antibodies is inherently classified as a passive immunotherapy (see instant Specification, Paragraph [0054]), this therefore reads on the method of the instant claim.
Regarding claim 12: Following the discussion of claim 2, Berenson et al further disclose that the subject suffers from cancer (Paragraphs [0076], [0117], [0176]). This therefore reads on the method of the instant claim.
Regarding claims 14 and 40: Following the discussion of claim 1, Berenson et al further disclose that the starting T cell count that is obtained from the subject is about 100 x 106 T cells and is expanded – via culturing and agitation – to a total of about 100 x 109 activated T cells (claim 14) (Paragraphs [0011], [0017], [0071], [0106], [0128]). As the expansion from 100 x 106 T cells to 100 x 109 T cells is greater than 10-fold, this therefore reads on the method of instant claim 40.
Regarding claim 23: As aforementioned in the discussion of claim 1, Berenson et al as modified by Kaiser et al render obvious the agitation of the contacted T cells at a speed of 300 rpm. As a rate of 300 rpm is sufficiently close to “about 250 rpm”, this therefore renders obvious the method of the instant claim. See MPEP § 2144.05.
Regarding claim 30: As aforementioned in the discussion of claim 1, Berenson et al as modified by Kaiser et al and Wahl et al render obvious the use of antibody-coated PDMS beads having a stiffness of 20 kPa. As a stiffness of 20 kPa is sufficiently close to the recited range of “between 10 kPa and 19 kPa”, this therefore renders obvious the method of the instant claim. See MPEP § 2144.05.
Regarding claim 32: Following the discussion of claim 1, Berenson et al further disclose that the surfaces – or beads – have a diameter of either 2.8 μm or 4.5 μm (Paragraph [0138]). As these are specific examples within the claimed range, this therefore reads on the method of the instant claim. See MPEP § 2131.03(I).
Regarding claim 33: Following the discussion of claim 1, Berenson et al further disclose that the surfaces – or beads – can also be comprised of alginate (Paragraph [0137]). This therefore renders obvious the method of the instant claim, as the ordinary artisan would recognize from the disclosure of Wahl et al that the stiffness of the bead and not its chemical structure affect the resulting characteristics of the T cells (Page 5909).
Regarding claim 34: As aforementioned in discussion of claim 1, Berenson et al disclose that the surfaces – or beads – are paramagnetic. Berenson et al further disclose that the surfaces – or beads – may instead comprise super-paramagnetic nanoparticles (Paragraphs [0095]-[0096], [0126]-[0127], [0137]-[0139]). This therefore reads on the method of the instant claim.
Regarding claim 37: Following the discussion of claim 1, Berenson et al further disclose that the T cells and anti-CD3/anti-CD28-conjugated beads are incubated together for a time period ranging from 30 minutes to 36 hours, and all integer values there between (Paragraphs [0091], [0117]). Berenson et al also disclose that the incubation period can include agitation (Paragraph [0106]). This therefore renders obvious the method of the instant claim, as the incubation agitation time of 12 hours to 36 hours overlaps with the range listed by Applicant and a prima facie case of obviousness exists in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art". See MPEP § 2131.03(II): In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997).
Claims 1-2, 4, 7-8, 10, 12, 14, 17, 23-24, 29, 30, 32-34, 37, 40, and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Berenson et al (US 2003/0119185 A1, of record) in view of Kaiser et al (US 2017/0037370 A1, of record) and Wahl et al (PNAS, 2019, of record), and further in view of Trickett et al (Journal of Immunological Methods, 2003, of record on IDS filed 08 December 2021).
The discussion of Berenson et al as modified by Kaiser et al and Wahl et al regarding claim 1 can be observed above and is relied upon herein, the content of which is incorporated herein in its entirety. Berenson et al as modified by Kaiser et al and Wahl et al render obvious claims 1-2, 4, 7-8, 10, 12, 14, 17, 23, 30, 32-34, 37, 40, and 86. Trickett et al is considered prior art under 35 U.S.C. 102(a)(1).
Regarding claims 24 and 29: As aforementioned in the discussion of claim 1 above, Berenson et al disclose contacting T cells with anti-CD3/anti-CD28 beads (Paragraphs [0011], [0014], [0019], [0065], [0068], [0077]). Berenson et al further disclose that the anti-CD3 antibody and the anti-CD28 antibody are present at a ratio of about 1:1 to about 1:100 (Paragraphs [0014], [0099]).
Berenson et al as modified by Kaiser et al and Wahl et al do not teach the concentration of the antibodies on the beads, nor that the beads comprise at least 200 fg of the anti-CD3 or anti-CD28 antibodies, as required by instant claims 24 and 29.
Trickett et al, however, disclose an anti-CD3/anti-CD28 antibody-coated bead comprising approximately 0.1 μg of anti-CD3 antibody and 0.5 μg of anti-CD28 antibody per each mg of beads, such that the anti-CD3 antibody and anti-CD28 antibody are present at a ratio of about 1:5 (Page 252, 4.1 Preparation of anti-CD3/CD28 beads).
Therefore, it would be prima facie obvious to modify the anti-CD3/anti-CD28 concentration on the beads of Berenson et al in view of Kaiser et al and Wahl et al to instead utilize the antibody concentrations provided in Trickett et al as the exemplary 1:5 antibody ratio, as doing so would a simple substitution of one known anti-CD3/anti-CD28 bead for another. See MPEP § 2143(I)(B). One of ordinary skill in the art before the effective filing date of the invention would have been able to substitute these anti-CD3/anti-CD28 beads and still yield predictable results, as all of Berenson et al, Kaiser et al, Wahl et al, and Trickett et al are concerned with the activation of T cells via the use of anti-CD3/anti-CD28 beads.
Consequently, Berenson et al as modified by Kaiser et al, Wahl et al, and Trickett et al render obvious an activation method wherein the anti-CD3/anti-CD28 beads (claim 29) have a final concentration of 45.6 fg antibody per bead when utilizing the 1:5 ratio. However, when extrapolated out to a 1:100 ratio, as detailed in Berenson et al, the final concentration is 760 fg antibody per bead. This is obtained via adding 0.1 μg of anti-CD3 antibody and 10 μg of anti-CD28 antibody per each mg of beads for a total of 10.1 μg of antibody per mg of beads, which is then multiplied by 7.6 mg per 108 beads. As 760 fg antibody per bead is greater than 200 fg antibody per bead, this therefore renders obvious the method of the instant claim 24.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA G WESTON whose telephone number is (571)272-0337. The examiner can normally be reached Monday-Thursday 8AM - 4PM (CT); Friday 8AM - 11AM (CT).
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/ALYSSA G WESTON/Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633