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 .1
Status of Claims
Claims 7-15, 20 and 22 are pending. Claims 7, 9, 12, 20 and 22 are examined. Claims 8, 10-11, and 13-15 remain withdrawn.2
Election/Restrictions
Applicant’s election without traverse of the species atypical PKC (aPKC) inhibitor ζ -Stat3
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, in the reply filed on Feb 23, 2026, is acknowledged. Claims 7, 9, 12, 20 and 22 read upon the elected species. Claims 8, 10-11, 13-15 are withdrawn as being drawn to a nonelected species.
Response to Arguments
Applicant's arguments to rebut the obviousness rejection, filed June 26, 2026, have been fully considered but they are not persuasive. See below Response to Attorney Arguments.
Applicant’s amendments, filed June 26, 2026, with respect to the objection to claim 7 has been fully considered and are persuasive. The objection of claim 7 has been withdrawn.
Claim Objections
Claim 12 is objected to because of the following informalities: the number nine “9” in line 1 is not underlined to note it has been added by amendment. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This application 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 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. “High mobility group box-1 is phosphorylated by protein kinase C zeta and secreted in colon cancer cells,” Biochemical and Biophysical Research Communications 424 (2012) 321-326. Lee is cited (as NPL Ref. 26) on one of the two IDS(s) submitted by Applicant on July 19, 2022.
Claim 7 is directed to a method of measuring susceptibility of colon cancer cells of a subject suffering from colon cancer to an aPKC inhibitor, the method comprising:
obtaining a colon cell sample from the subject suffering from colon cancer, wherein the colon cell sample comprises colon cancer cells and adjacent normal colon epithelial cells; measuring expression of one or more aPKCs in the colon cancer cells and in the adjacent normal colon epithelial cells; in response to determining that expression of the one or more aPKCs is higher in the colon cancer cells than in the adjacent normal colon epithelial cells,
exposing a portion of the colon cancer cells of the colon cell sample to the aPKC inhibitor while leaving another portion of the colon cancer cells of the colon cell sample untreated;
detecting cell proliferation, expression, and activation of the one or more aPKCs in treated and untreated colon cancer cells; and
selecting the subject as having a cancer susceptible to the aPKC inhibitor by detecting a reduction in proliferation, expression and activation of the one or more aPKCs in treated colon cancer cells compared to untreated colon cancer cells, wherein the reduction indicates the subject's cancer is susceptible to the aPKC inhibitor.
Regarding claim 7 and the limitations of selecting a claimed colon cancer subject in need and detecting aPKC overexpression and activation in a subject’s cells Lee teaches a demonstration of overexpression and activation of PKC-ζ in colon cancer tissues, see abstract. Lee suggests studying colon cancer using HCT116 cell line (see Section 2.1 page 372) to suggest obtaining/sampling colon cancer cells from a subject in need.
Regarding the limitation of exposing colon cancer cells to an atypical PKC inhibitor, Lee teaches the exposure of HCT116 colon cancer cells to PKC inhibitors (GÖ6983 and rottlerin) to inhibit PKC and to decrease HMGB1 secretion See Figure 2 page 323. See also Section 3.2, Atypical PKCs bind to HMBG1 in HCT116 cells, page 322.
Lee concludes that PKC-ζ phosphorylates HMGB1, and the phosphorylation of specific serine residues in the nuclear localization signal regions enhances HMGB1 secretion in colon cancer cells, see abstract.
With regard to the obtaining from colon cancer subject patients and measuring step (detecting cell proliferation, expression, and activation of one or more aPKCs in treated cells), Lee teaches the evaluation of PKC-ζ in colon cancer tumor tissue, versus adjacent normal mucosa, where specimens from 30 cancer patients with matched normal mucosae. See Section 3.4 PKC- ζ expression in tumor tissues, page 324.
See also Section 2.4. Selection of tissue samples at page 322, column 1. 4
Lee teaches that the most critical PKC isotype that regulates secretion of HMGB1 (a protein overexpressed and secreted in cancer cells) was PKC-ζ, which was identified by using PKC inhibitors and siRNA experiments, see abstract and page 322, Section 2.6. Further, Lee teaches that PKC- ζ is critical for HMGB1 secretion, see Section 3.3, pages 323-324. Lee identifies these PKC inhibitors (Gö6983, ATG and rotterlin) as being atypical PKC inhibitors, see Section 3.2 entitled Atypical PKC’s bind to HMGB1 in HCT116 cells.
It is noted that Lee does not expressly teach a colon cell sample that comprises colon cancer cells and adjacent normal colon epithelial cells; measuring expression of one or more aPKCs in the colon cancer cells and in the adjacent normal colon epithelial cells; in response to determining that expression of the one or more aPKCs is higher in the colon cancer cells than in the adjacent normal colon epithelial cells,
portioning a sample of colon cancer cells into some that are exposed to an aPKC inhibitor and comparing expression/activation of aPKC in the two samples.
Prior to the filing of the instant application a PHOSITA following the teachings of Lee would have found it prima facie obvious to arrive at the claimed invention’s method, where Lee teaches sampled colon tumor cells, Lee teaches evaluation of 30 paired fresh frozen colon tissues and matched normal mucosa tissues, as well as using a colon cell model, exposed these cells to aPKC inhibitors and took measure of aPKC expression and activation before and after exposure as well as comparing them to an unexposed control. It would be routine to use and substitute an unexposed control sample, versus the same cells measured for aPKC activation pre-exposure. See MPEP 2143(b) noting [s]imple substitution of one known element for another to obtain predictable results (substituting pre-PKC inhibitor exposure colon cancer cells, as a control, with non-exposed colon cancer cells, as a control, to measure levels of aPKC expression and activation due to aPKC inhibitor exposure.
Obtaining a colon cell sample (with normal adjacent epithelial cells and colon cancer cells) would be routinely optimized by a person having ordinary skill in the art (PHOSITA), where levels of aPKC are noted to be measured by levels of HMGB1 secretion pre and post levels of exposure, and measured to compare the two as claimed. The art teaches that colon cancer cells are known to have elevated levels of aPKC as opposed to normal epithelial cells. The art teaches the use of PKC inhibitors with colon cancer cells. A PHOSITA would routinely optimize to use controls of non-exposed tumor cells obtained from the same tumor sample, where Lee teaches exposure cells to an aPKC inhibitor to measure its effects in terms of PKC expression and activation as measured by HMGB1 secretion before and after exposure. While there is not an explicit recital of a cell sample with both cancer and non-cancerous cells, measurement of aPKC expression, this limitation would be routinely optimized by a PHOSITA where aPKC is known to be higher in cancer cells, per Lee vs. normal, non-cancerous cells.
Claims 7, 9 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. “High mobility group box-1 is phosphorylated by protein kinase C zeta and secreted in colon cancer cells,” Biochemical and Biophysical Research Communications 424 (2012) 321-326 in view of Mayanglambam et al. Differential dephosphorylation of the Protein Kinase C-zeta (PKC ζ) in an integrin αIIbβ3-dependent manner in platelets, Biochem Pharmacol. 2011 September 1; 82(5): 505–513. Mayanglambam is cited on the PTO-892 form.
While claims 7 and 9 disclose the claimed method of measuring the susceptibility of colon cancer cells of a subject suffering from colon cancer to an atypical PKC (aPKC) inhibitor as per Lee, it does not teach activation of (aPKC) inhibitor ζ -Stat is detected as increased phosphorylation of PKC ζ at Thr410.
Regarding claim 12 directed to the increased phosphorylation of PKC- ζ detected at Thr410, Mayanglambam teaches it is well established that the mechanism of activation of PKC- ζ has long been known to demonstrate its high phosphorylation status at the activation loop threonine 410 (T410). See abstract. Accordingly, prior to the filing date of the application, a PHOSITA following the teachings of Lee (noting overexpression and activation of PKC-ζ in colon cancer tissues, and therefore treat colon cancer via its inhibition) and Mayanglambam noting PKC- ζ activation via increased phosphorylation at Thr410.
Claims 7, 9, 20 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. High mobility group box-1 is phosphorylated by protein kinase C zeta and secreted in colon cancer cells Biochemical and Biophysical Research Communications 424 (2012) 321-326 in view of US Pub 2017/0348336 A1, claiming priority to June 2, 2016. US Pub ‘336 is cited on the PTO-892 form.
While claims 7 and 9 disclose the claimed method of measuring the susceptibility of colon cancer cells of a subject suffering from colon cancer to an atypical PKC (aPKC) inhibitor, it does not teach the particular atypical PKC (aPKC) inhibitor ζ -Stat as recited in claim 20 or the limitations of claim 22.
To correct this deficiency regarding claim 20, US Pub '336 teaches the treatment of a cancer (melanoma) in a subject in need thereof, the method comprising administering a therapeutically-effective amount of an inhibitor of an atypical protein kinase C (aPKC), see claim 1.
US Pub '336 teaches the particular expression of PKC- ζ (aka PKC zeta) in cancer (melanoma), see paragraph 15.
US Pub '336 teaches in particular, applicant's elected species of atypical PKC inhibitor, ζ -Stat is a preferred embodiment, see paragraph 35 and claims 9 and 18.
With regard to the selection of a cancer patient having an aPKC inhibitor susceptible cancer, this is rendered obviously Lee and US Pub ‘336 teaching the targeting of such a colon cancer with n aPKC inhibitor, in particular ζ -Stat.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of Lee to arrive at the claimed invention’s method, where Lee teaches sample colon tumor cells, as well as using a colon cell model, exposed them to aPKC inhibitors and took measure of aPKC expression and activation before and after exposure (equivalent to a control versus exposed cell), where US Pub ‘336 teaches the particular elected species of aPKC inhibitor, ζ -Stat as detailed above.
Regarding claim 22 reciting further treating the subject with surgery, radiation therapy, or immunotherapy where the cancer is not susceptible to the aPKC inhibitor, US Pub ‘336 teaches its PKC inhibitor, may be administered with a surgery, a radiation therapy, an immunotherapy or a combination thereof. See paragraph 120.
While there is a possible co-administration with an aPKC inhibitor per US Pub ‘336, it would be well within the purview of a PHOSITA to treat via surgery, radiation etc. where the cancer turns out to be non-susceptible to a PKC inhibitor therapy.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states Lee does not disclose that integrated workflow. Rather, Lee separately reports inhibitor studies in the HCT116 colon cancer cell line and separate comparisons of tumor tissue versus matched normal mucosa; those separate disclosures do not teach the claimed arrangement of steps in a single subject-specific susceptibility method. The Attorney response states claim 9 remains patentable for the same reasons.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Lee teaches evaluation of 30 paired fresh frozen colon tissues and matched normal mucosa tissues, as well as using a colon cell model, exposed these cells to aPKC inhibitors and took measure of aPKC expression and activation before and after exposure as well as comparing them to an unexposed control. It would be routine to use and substitute an unexposed control sample, versus the same cells measured for aPKC activation pre-exposure. See MPEP 2143(b) noting [s]imple substitution of one known element for another to obtain predictable results (substituting pre-PKC inhibitor exposure colon cancer cells, as a control, with non-exposed colon cancer cells, as a control, to measure levels of aPKC expression and activation due to aPKC inhibitor exposure.
In response to applicant's argument that Lee is nonanalogous art (Lee does not disclose integrated workflow; HCT116 inhibitor studies and tumor tissue vs normal matched mucosa tissue; susceptibility assay of a subject’s colon cancer cell only after an initial tumor vs. adjacent normal tissue/cell comparison; lack of detecting step of claim 7; different materials used, inhibitor study used HCT116, a commercial colon cancer cell line AND paired tissue specimens for PKC zeta express), it has been held that a prior art reference must either be in the field of applicant’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the applicant was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, despite any differences from the teaching of the prior art Lee, as detailed above, the rationale for the prima facie case has been established above. Furthermore, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
The Attorney response states amended claim 12 is further distinguished from Lee by now requiring that activation of PKC-ζ is detected as increased phosphorylation of PKC-ζ at Thr410. As detailed above, Mayanglambam teaches it is well established that the mechanism of activation of PKC- ζ has long been known to be demonstrated its high phosphorylation status at the activation loop threonine 410 (T410). See abstract. Accordingly, prior to the filing date of the application, a PHOSITA following the teachings of Lee (noting overexpression and activation of PKC-ζ in colon cancer tissues, and therefore treat colon cancer via its inhibition) and Mayanglambam noting PKC- ζ activation via increased phosphorylation at Thr410.
Conclusion and Correspondence
No claims are allowed. 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 WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 CONTINUING DATA
This application is a DIV of 15/643,117 07/06/2017 PAT 11337944
15/643,117 has PRO 62/359,496 07/07/2016
2 Support for the amendments can be found in at least original claims 7, 9, 12, 20 and 22 and paragraphs [0079]-[0085], [0087]-[0093], [0096]-[0104], [Ol l 7]-[0122], [0128], and [0156]- [ 0160] of the published application
3 CAS Reg. No. 3316-02-7, 8-Hydroxy-1,3,6-naphthalenetrisulfonic acid.
4 For the analysis of PKC-f and phosphorylated PKC-f expression in human tissue samples, 30 paired fresh frozen colon cancer tissues and matched normal mucosa tissues were selected.
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