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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8-27-25 has been entered.
Claims 1-12, 14-21, 67-75 are pending.
Claims 1-12 and 14-21 are under examination as they read methods of treating neoplastic disease.
Claims 67-75 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1-17-24.
The prior rejection under 35 USC § 103 based on Mumm et al. (WO2017123557)…, has been with withdrawn in view of applicant’s claim amendments.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-12 and 14-16 stand rejected under 35 U.S.C. 103 as being unpatentable over Mumm et al. (WO2016191587) in view of Chan et al. (JOURNAL OF INTERFERON & CYTOKINE RESEARCH, Volume 35, Number 12, pages 948-955 (2015))), Sommermeyer et al. (Leukemia (2016) 30, 492–500), Casati et al. (Cancer Immunol Immunother (2013) 62:1563–1573)(all of record).
Applicant asserts: “…as Applicant understands it, the position of the Office is that the examples of the present specification are consistent with the knowledge of prior art and therefore support a prima facie case of obviousness.”
The undersigned disagrees with applicant’s assertion that the prior Office Action took the position that because “the examples of the present specification are consistent with the knowledge of prior art” they “therefore support a prima facie case of obviousness.”
This was not what was said in the prior Office Action. Rather, here are two relevant quotes from the prior Office Action:
“However, most of applicant's assertions about the specification Examples are either inaccurate
and/or do not appear to be undermine or otherwise call into question the outstanding prima facie
obviousness rejection. Rather, the teachings of the specification Examples appear to be
consistent with the knowledge of the prior art that supports the prima facie case of obviousness.”
“Thus, if anything, the teachings of specification Example 3 appear to be consistent with the
knowledge of the prior art that supports the prima facie case of obviousness.”
By contrast to applicant’s assertion, the prior Office Action did not say that the teachings of the specification, per se, support the case of prima facie obviousness but instead specified that certain teachings of the specification are consistent with the prior art teachings upon which the case of prima facie obviousness was based.
That said, applicant goes on to argue that “The prior art does not teach or suggest combining an IL-10 pretreatment to anti-CD19 CAR-T cells taught in the specification at pages 130 to 134 and
Examples 13, 14, 15 and 16…. Further, the prior art, alone or in combination, would not have provided the motivation for one skilled in the art to pretreat an anti-CD19 CAR-T cell with an IL10 agent prior to administration to a patient suffering from a neoplastic disease.”
Applicant's arguments have been considered but have not been found convincing essentially for the reasons of record as described below.
Mumm teaches the production of CAR-T cells for use in the context of treating cancer via adoptive immunotherapeutic administration of a therapeutically effective amount of said CAR-T cells and of IL-10 (see, e.g., at paragraphs 0007, 0011, 0021, 0029, 0031). At paragraphs 0008, Mumm teaches “…the data presented herein suggest that an IL-10 agent may be used in conjunction with CAR-T T cell therapy to prevent or limit activation-induced cell death while enhancing CD8+ T cell function and survival.” With respect to the particular type of T-cell to be used for CAR T cell therapy, Mumm teaches obtaining memory CD8+ T cells, including for example central memory T cells, from the patient and genetically modifying said T cells with a CAR having tumor-binding extracellular domain, such as an anti-tumor antigen binding scFv, joined to transmembrane domain, an “intracellular signaling domain” such as human CD3zeta chain, and a “co-stimulatory domain” such as the CD28 domain (see paragraphs 0098, 00100-00103, 00105-00107).
At paragraphs 0027-0029 Mumm further teaches:
“[0027] In each of the aforementioned embodiments, the target cell population may comprise a tumor antigen. Vigneron, N. et al. ((15 July 2013) Cancer Immunity 13 : 15) describe a database of T cell - defined human tumor antigens containing over 400 tumor antigenic peptides. Examples of tumor antigens include, but are not limited to, CD19, CD20, CD22, RORl, mesothelin, CD33/IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, or any combination thereof.
[0028] The present disclosure also contemplates the use of CAR-T cell therapy for the treatment or prevention of a disease, disorder or condition (e.g., a cancer-related disorder) in a subject in combination with the administration of an IL-10 agent (e.g., PEG-IL-10) or the introduction of a vector that expresses an IL-10 agent.
[0029] A particular embodiment comprises methods of treating a subject having a cancer-related disease, disorder or condition (e.g., a tumor), comprising a) introducing to the subject a therapeutically effective plurality of cells genetically modified to express a chimeric antigen receptor, wherein the chimeric antigen receptor comprises at least one antigen-specific targeting region capable of binding to the target cell population, and wherein the binding of the chimeric antigen receptor targeting region to the target cell population is capable of eliciting activation-induced cell death; and b) administering to the subject a therapeutically effective amount of an IL-10 agent sufficient to prevent or limit the activation -induced cell death. In particular embodiments, the subject being treated has an immune-related disease, disorder or condition or another disease, disorder or condition described herein.”
In Examples 2 and 3 Mumm teaches the following (emphasis added):
“Given that CAR-T T cells are derived from memory CD8+ T cells, the effect of PEG-IL-10 on memory CD8+ T cells was assessed in vitro using standard methodology, an example of which is described herein. As indicated in Figure 2, PEG-IL-10 preferentially enhances IFNγ production in memory CD8+T cells (CD45RO+) and not naive CD8+ T cells. These data are consistent with the effect of PEG-IL-10 to enhance the function of activated memory CD8+ T cells.”
“As described herein, CAR-T cell therapy is derived from memory CD8+ T cells. In order to be effective, infused memory CD8+ T cells must not only exhibit cytotoxicity, but must also persist… However, repeated activation of T cells leads to activation-induced cell death, which decreases the number of cells and thus the overall therapeutic efficacy.
Using the procedure described herein, the activation-induced cell death of human CD45RO+ memory CD8+ T cells from two donors was determined with and without treatment with PEG-IL-10. As indicated in Figure 3, treatment of human CD45RO+ memory CD8+ T cells with PEG-IL-10 after two rounds of TCR and co-stimulation - induced activation resulted in a greater number of viable cells. These data indicate that PEG-IL-10 is capable of limiting activation-induced cell death, thus resulting in a greater number of activated memory T cells to persist. These observations suggest that the use of PEG-IL-10 in combination with CAR-T cell therapy provides additional clinical benefit.”
The results of working Examples 2 and 3 are summarized in paragraphs 00115 and 00118 at page 26 (emphasis added):
“[00115] While IL-10 has been discussed in the context of enhancement of activation-induced
cell death…in vitro and in vivo data presented herein indicate that an IL-10 agent (e.g., PEG-IL-10) may be combined with CAR-T T cell therapy to prevent or limit activation-induced cell death while enhancing CD8+ T cell function and survival.”
…..
“[00118] Because CAR-T T cells are derived from memory CD8+ T cells, the effect of
PEG-IL-10 on memory CD8+ T cells was assessed in vitro. The data presented in Example 2
are consistent with the effect of PEG-IL-10 to enhance the function of activated memory CD8+ T cells.”
Finally, note that at paragraph 0012 Mumm teaches: “In certain embodiments of the present disclosure, the IL-10 agent enhances the function of activated memory CD8+ T cells. In other embodiments, the amount of the IL-10 agent administered is sufficient to enhance cytotoxic function,” and further at paragraph 0056 Mumm teaches “The terms "administration", "administer" and the like, as they apply to, for example, a subject, cell, tissue, organ, or biological fluid, refer to contact of, for example, IL-10 or PEG-IL-10), a nucleic acid (e.g., a nucleic acid encoding native human IL-10); a pharmaceutical composition comprising the foregoing, or a diagnostic agent to the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.”
However, Mumm does not explicitly teach a method of treating a mammalian subject suffering from a neoplastic disease the method comprising:
a. obtaining a sample of T-cells derived from the patient;
b. transducing a fraction of T-cells in the sample with a vector, the vector comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR) the nucleic acid sequence being in operable association with one or more control elements to effect transcription and translation of the nucleic acid sequence encoding a chimeric antigen receptor (CAR) in a T-cell, so as to generate a population of T-cells expressing the CAR;
c. isolating the T-cells expressing the CAR (CAR-T cells) ;
d. culturing the anti-CD19 CAR-T cells ex vivo in the presence of an IL-10 agent, wherein between 1 ng/ml and 1000 ng/ml of the IL-10 agent was added to the CAR-T cells; and
e. administering the anti-CD19 CAR-T cells from step (d) to the mammalian subject;
as well as
the method having steps (a)-(e) above and further comprising step (f),
“administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising an IL-10 agent,
wherein the IL-10 agent of step (d) and the IL-10 agent of the pharmaceutical formulation of step (f) are different IL-10 agents; and
wherein the first IL-10 agent of step (d) is rhIL-10 and the pharmaceutical formulation of IL-10 agent of step (f) comprises a PEGylated IL- 10 agent,”
as recited in claim 5.
The Abstract of Chan teaches: “In this study, we show that PEG-rHuIL-10 exerts immune inhibitory effects on human peripheral blood mononuclear cell (PBMC) bulk cultures and stimulatory effects in CD8 T cells within the same culture. Also, in isolated CD8 T cells, PEG-rHuIL-10 potentiates prototypic Tc1 cytokine IFN-g expression and induces perforin and granzyme B secretion.”
In the 1st paragraph of the Results section through the paragraph bridging pages 949-950 Chan teaches human primary CD8+ cells can be made to over-produce IFNγ when cultured in the presence of PEG-rHuIL10 either prior to or subsequent to plate-bound anti-CD3/anti-CD28 activation/proliferation; moreover, as described at page 951 col. bridging paragraph – page 953, 1st full paragraph, PEG-rHuIL-10 does not directly induce substantial amounts of IFNγ but instead “potentiates” treated cells such that they produce more IFNγ upon TCR ligation.
As described at page 953, 1st full paragraph and as shown in Fig. 1G, “This potentiation was predominantly found in the CD45RO+ CD8 T-cell population….”
Moreover, as further described in the 2nd full paragraph of page 953, “In activated CD8 T cells,
treatment with PEG-rHuIL-10 increased the percentage of cells containing intracellular perforin….,” and “CD8 T cells had increased intracellular granzyme B compared to untreated cells….,” (pointing to the in vitro assays displayed in Figs 2A-D) which leads Chan to conclude “These data indicate that PEG-rHuIL-10 induces cytotoxic proteins in CD8 T cells, which may lead to enhanced cell cytotoxicity.”
Notably, it would have been obvious to the ordinarily skilled artisan that the teachings of Chan were consistent with the teachings of Mumm at paragraph 0012 (emphasis added): “IL-10 agent enhances the function of activated memory CD8+ T cells. In other embodiments, the amount of the IL-10 agent administered is sufficient to enhance cytotoxic function.”
Sommermeyer describes how among the various CD4 and CD8 memory T cell subsets present in human PBMC, the CD8+ central memory T cell subset (Tcm) has the greatest therapeutic potential due to its anti-tumor potency and its ability to persist in vivo (see, e.g., page 494-495 bridging paragraph; page 496-497 bridging paragraph; page 497-498 bridging paragraph; page 498, right col., 1st full paragraph).
The title of Casati is as follows: “Clinical-scale selection and viral transduction of human naïve
and central memory CD8+ T cells for adoptive cell therapy of cancer patients.”
The final paragraph of the Introduction of Casati states: “We show that TN and TCM cells sorted from blood of metastatic melanoma patients can efficiently be expanded and transduced under these conditions. Importantly, TN and TCM cells show minimal effector differentiation and
lower levels of markers correlating with terminal differentiation when stimulated with TransAct or αCD3/αCD28-conjugated micron-sized particles (MACSiBeads). Taken together, our study provides a well-defined technological platform for the GMP sorting, expansion and genetic engineering of defined T cell subsets for use in clinical trials to treat patients with cancer.”
At page 1570, right col., 2nd – 4th full paragraphs Casati concludes that their cGMP compliant expansion protocol allows for the isolation, activation, transduction and expansion of sufficient cells for adoptive immunotherapy purposes. Similar conclusions are made in the final summary paragraph in the right column of page 1571.
Notably, as is made clear throughout the teachings of Sommermeyer and Casati, viral transduction is the most commonly used method for introduction of an expression vector in T cells, including patient T cells (see, e.g., Casati “T cell stimulation and transduction” at page 1565 and “Optimized reagents for in vitro activation and TCR transduction of T cell subsets” at page 1567-69l; Sommermeyer at page 493, last full paragraph; at page 493-94 bridging paragraph; at page 497 col. bridging paragraph).
Given the teachings of Mumm, Chan, Sommermeyer and Casati it would have been obvious to the ordinarily skilled artisan that (i) CAR-T cells comprising an anti-CD19 scFv based “targeting region” and further comprising a CD28 signaling domain should be derived from transduction of central memory CD8+ T cells (Tcm) with a suitable CAR expression vector so as to optimize their in vivo effectiveness, and (ii) incubation with IL-10 after activation of central memory CD8+ T cells with anti-CD3/anti-CD8 antibody should effectively “potentiate” the ability of said cells to mediate cytotoxicity upon exposure to their target antigen.
Therefore, it would have been obvious to the ordinarily skilled artisan, and the ordinarily skilled artisan would have been motivated to produce CD8+ Tcm engineered to contain a CAR comprising an anti-CD19 scFv based “targeting region” and a CD28 signaling domain, said CD19-targeting, engineered Tcm having optimal cytotoxicity against cells that express their cognate target antigen. In particular, it would have been obvious to the ordinarily skilled artisan that even after T-cell activation, transduction and expansion, incubation of CAR-Tcm with IL-10 prior administration to a subject in need thereof will potentiate the ability of CAR Tcm to mediate cytotoxicity upon exposure to their target antigen.
Likewise, given the reference teachings it further would have been obvious to the ordinarily skilled artisan that treatment of a cancer patient with Tcm genetically engineered to express a CAR comprising an anti-CD19 scFv based “targeting region” and a CD28 signaling domain could be improved by further administering IL-10 to said cancer patient so as to “prevent or limit activation-induced cell death while enhancing CD8+ T cell function and survival” as taught by Mumm.
As to administering a pharmaceutical formulation of IL-10 in an amount sufficient to maintain a serum trough concentration of at least 0.01, 0.05, 0.1 or 0.5 ng/mL for at least 72 hours (see claims 8-11), Mumm teaches administration of IL-10 to a subject in amount sufficient to achieve a serum trough concentration ≥ 0.01, 0.05, 0.1 or 0.5 ng/mL for at least 72 hours at paragraphs 0014-0015.
Insofar as Mumm does not explicitly teach, e.g., “administering of a pharmaceutical formulation comprising the IL-10 agent is sufficient to maintain a serum trough concentration of the IL-10 agent in the subject of at least 0.01 ng/ml over a period of at least 72 hours” as recited for example in claim 8 for example, it is submitted that one of ordinary skill in the art would have been motivated to determine the optimum or workable range for any therapeutic agent to be administered to a patient need thereof. In this regard, applicant’s attention is drawn to MPEP 2144.05(II)(A):
“II. Routine Optimization
A. Optimization Within Prior Art Conditions or Through Routine Experimentation
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) (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 re Hoeschele, 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 re Kulling, 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.’).”
Although this passage does not specifically teach, any particular dosage regimen for the effective administration of IL-10 to a cancer patient, this passage nonetheless points to numerous variables that affect the function of inventions, such as concentration of reagents. Furthermore, this passage indicates that optimization of such variables is often an obvious activity for the ordinarily skilled artisan.
Additionally, as set forth in MPEP 2144.05(II)(B), “… In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because "obvious to try" is not a valid rationale for an obviousness finding. However, in KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.”
Thus, given the teachings of Mumm it would have been prima facie to try different dosage regimens of IL-10 so as to identify the dose sufficient to maintain therapeutic efficacy in any given cancer patient over any given period of time, such as over a 72 hour time period.
With respect to the type of IL-10 agent to be used when pre-treating CD8+ Tcm engineered to contain a CAR comprising an anti-CD19 scFv based “targeting region” and a CD28 signaling domain prior to administration to a patient having a neoplastic disease such as cancer as recited in claims 2-7, Mumm teaches various advantages to pegylation of therapeutic proteins such as IL-10, e.g., better efficacy against certain cancers than unpegylated IL-10 and improved circulating half-life and improved physical and thermal stability compared to unpegylated IL-10 (see paragraph 00175-176).
Notably, in working examples 2 and 3, Munn shows that pegylated IL-10 functions in vitro to enhance the cytotoxic activity of active memory CD8+ T cells.
The results of working Examples 2 and 3, which make use of pegylated IL-10, are summarized in paragraphs 00115 and 00118 at Munn page 26 (emphasis added):
“[00115] While IL-10 has been discussed in the context of enhancement of activation-induced
cell death…in vitro and in vivo data presented herein indicate that an IL-10 agent (e.g., PEG-IL-10) may be combined with CAR-T T cell therapy to prevent or limit activation-induced cell death while enhancing CD8+ T cell function and survival.”
…..
“[00118] Because CAR-T T cells are derived from memory CD8+ T cells, the effect of
PEG-IL-10 on memory CD8+ T cells was assessed in vitro. The data presented in Example 2
are consistent with the effect of PEG-IL-10 to enhance the function of activated memory CD8+ T cells.”
Thus, with respect to claim 3, given the teachings of Munn it would have been obvious to the ordinarily skilled artisan that PEG-IL-10 could be used both to enhance the cytotoxic function and to limit activation-induced death of memory CD8+ T cells in vitro, as well as administered in vivo where the improved circulating half-life of PEG-IL-10 would be advantageous for either ensuring persistent levels of IL-10 activity during the CAR T-cell cancer cell killing phase, and/or for decreasing the cost of maintaining such levels of IL-10 activity during the CAR T-cell cancer cell killing phase (insofar as fewer doses of PEG-IL-10 would be necessary to ensure adequate levels of IL-10 activity for support CAR T-cell cancer cell killing).
That said, with respect to claims 4 and 5, given that the ordinarily skilled artisan would not consider the improved circulating half-life of pegylated IL-10 to be important for use of IL-10 in vitro, it also would have been obvious to the ordinarily skilled artisan that non-pegylated, recombinant human IL-10 (see Munn paragraph 0087) could be used for the in vitro pre-incubation of CAR T-cells prior to administering CAR T-cells with pegylated IL-10 which exhibits improved circulating half-life. One motivation the ordinarily skilled artisan may have for using non-pegylated, recombinant human IL-10 in vitro is that such a molecule will be easier and cheaper to produce than pegylated IL-10.
With respect to claims 6-7, as described at paragraphs 0088-0089 of Mumm,
“…the terms ‘pegylated IL-10’ and ‘PEG-IL-10’ refer to an IL-10 molecule having one or more polyethylene glycol molecules covalently attached to at least one amino acid residue of the IL-10 protein, generally via a linker, such that the attachment is stable. The terms ‘monopegylated IL-10’ and ‘mono-PEG-IL-10’ indicate that one polyethylene glycol molecule is covalently attached to a single amino acid residue on one subunit of the IL-10 dimer, generally via a linker. As used herein, the terms ‘dipegylated IL-10’ and ‘di-PEG-IL-10’ indicate that at least one polyethylene glycol molecule is attached to a single residue on each subunit of the IL-10 dimer, generally via a linker.
In certain embodiments, the PEG-IL-10 used in the present disclosure is a monoPEG-IL-10 in which one to nine PEG molecules are covalently attached via a linker to the alpha amino group of the amino acid residue at the N-terminus of one subunit of the IL-10 dimer. Monopegylation on one IL-10 subunit generally results in a non-homogeneous mixture of nonpegylated, monopegylated and dipegylated IL-10 due to subunit shuffling. Moreover, allowing
a pegylation reaction to proceed to completion will generally result in non-specific and multipegylated IL-10, thus reducing its bioactivity. Thus, particular embodiments of the present
disclosure comprise the administration of a mixture of mono- and di-pegylated IL-10 produced
by the methods described herein.”
Moreover, at paragraph 0019 Mumm teaches: “The PEG-IL-10 agent can comprise at least one PEG molecule covalently attached to at least one amino acid residue of at least one subunit of IL-10 or comprise a mixture of mono-pegylated and di-pegylated IL-10 in other embodiments.”
At paragraph 00251 Mumm additionally teaches: “…Pegylated IL-10 as described herein may be synthesized by any means known to the skilled artisan. Exemplary synthetic schemes for producing mono-PEG-IL-10 and a mix of mono-/di-PEG-IL-10 have been described (see, e.g., U.S. Patent No. 7,052,686; US Pat. Publn. No. 2011/0250163; WO 2010/077853). Particular embodiments of the present disclosure comprise a mix of selectively pegylated mono- and di-PEG-IL-10.”
Finally, at paragraph 0090 Mumm teaches: “In particular embodiments, the average molecular weight of the PEG moiety is between about 5kDa and about 50kDa. Although the method or site of PEG attachment to IL-10 is not critical, in certain embodiments the pegylation does not alter, or only minimally alters, the activity of the IL-10 agent.”
Given the teachings of Mumm set forth above, it would have been obvious to the ordinarily skilled artisan that mono- and/or di-pegylated IL-10 could be used to increase CAR T-cell cytotoxicity in vitro or in an in vivo setting with a reasonable expectation of success.
In conclusion, in view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim(s) 17-21 stand rejected under 35 U.S.C. 103 as being unpatentable over Mumm et al. (WO 2016/191587) in view of Chan et al. (JOURNAL OF INTERFERON & CYTOKINE RESEARCH, Volume 35, Number 12, pages 948-955 (2015)), Sommermeyer et al. (Leukemia (2016) 30, 492–500) and Casati et al. (Cancer Immunol Immunother (2013) 62:1563–1573) as applied to claims 1-12 and 14-16 above, and as further evidenced by the teachings of Lhuillier et al. (Seminars in Cancer Biology 52 (2018) 125–134) and Palmer et al. (Cell 171, 1678–1691, 2017)(all of record).
As to administering IL-10 and/or chemotherapeutics and/or an immune checkpoint modulator (claims 17-21) to a patient in need thereof in conjunction with CD8+ Tcm engineered to contain a CAR comprising an anti-CD19 scFv based “targeting region” and a CD28 signaling domain, Mumm teaches, e.g., at paragraph 00233-234 (emphasis added),
“[00233] In conjunction with the CAR-T T cell therapy described herein, the present disclosure provides methods for treating and/or preventing a proliferative condition, cancer, tumor, or precancerous disease, disorder or condition with an IL-10 agent (e.g., PEG-IL-10) and at least one additional therapeutic or prophylactic agent(s) or diagnostic agent exhibiting a desired activity. Some embodiments of the present disclosure contemplate the use of traditional chemotherapeutic agents ( e.g., alkylating agents, nitrogen mustards, nitrosureas, antibiotics, anti-metabolites, folic acid analogs, purine analogs, pyrimidine analogs, antihormonal agents and taxoids). Other embodiments of the present disclosure contemplate methods for tumor
suppression or tumor growth comprising administration of an IL-10 agent described herein in
combination with a signal transduction inhibitor (e.g., GLEEVEC or HERCEPTIN) or an
immunomodulator to achieve additive or synergistic suppression of tumor growth.
[00234] In conjunction with the CAR-T T cell therapy described herein, the present
disclosure also provides methods for treating and/or preventing immune- and/or inflammatory- related diseases, disorders and conditions, as well as disorders associated therewith, with an IL10 agent (e.g., PEG-IL-10) and at least one additional agent(s) or diagnostic agent exhibiting a desired activity. Examples of therapeutic agents useful in combination therapy include, but are
not limited to non-steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2)
inhibitors, steroids, TNF antagonists (e.g., REMICADE and ENBREL), interferon-β1a
(AVONEX), interferon-β1b (BETASERON), and immune checkpoint inhibitors (e.g., YERVOY).”
Thus, it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to administer CD8+ Tcm engineered to contain a CAR comprising an anti-CD19 scFv based “targeting region” and a CD28 signaling domain in combination with IL-10 and/or chemotherapeutics and/or an immune checkpoint modulator so as to (i) limit activation-induced cell death via the IL-10 (see, e.g., at paragraph 00271 of Mumm), and (ii) attack the cancer or tumor cells with mechanistically distinct modalities which has the potential to mitigate drug-induced resistance, drug toxicity and/or yield potentially synergistic therapeutic effects (see, e.g., Lhuillier et al., Seminars in Cancer Biology 52 (2018) 125–134, at pages 125-126 col. bridging paragraphs on each; Palmer et al., Cell 171, 1678–1691, 2017, at pages 1678-79 Abstract and Introduction).
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644