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 .
Response to Amendment
The amendment filed 07/06/2026 is acknowledged. Regarding the Office action mailed 01/06/2026:
The objections regarding sequence disclosure issues and hyperlinks are withdrawn in view of the provision of the sequence listing and amendments to the specification.
The rejection under 35 USC 102(a)(1) over Regev (US 2021/0047694) is withdrawn, as the rejection does not mention Spp1 or Lynch syndrome, each of which has been recited in amended claim 1, upon which all other claims now depend.
The rejection under 35 USC 102(a)(1) over Pogue-Geile (US 2019/0076391) is withdrawn, as the rejection does not mention detecting protein, or Lynch syndrome, each of which has been recited in amended claim 1, upon which all other claims now depend.
For the same reasons, all previous rejections under 35 USC 103 based on each of these references are withdrawn.
New grounds of rejection are set forth below.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 26 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 has been amended to require the patient has Lynch syndrome. Lynch syndrome is a deficiency in the mismatch repair system (MMR) caused by a mutation in one or more of the genes required for MMR; see Lynch (2015), attached.
As a result, claim 26 does not appear to be further limiting since the cancer would necessarily be MMR-d in a Lynch syndrome patient.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claim(s) 1, 20, 25, 26 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Macina (US 2010/0009905) in view of Agrawal (Journal of the National Cancer Institute 94(7):513-521 (2002)).
Regarding claim 1, Macina disclosed (para 0008): “Once colon cancer has been diagnosed, treatment decisions are typically made in reference to the stage of cancer progression.”
Macina disclosed (para 0020): “Accordingly, there is a great need for more sensitive and accurate methods for predicting whether a person is likely to develop colorectal cancer, for diagnosing colorectal cancer, for monitoring the progression of the disease, for staging the colorectal cancer, for determining whether the colorectal cancer has metastasized, and for imaging the colorectal cancer.”
To this end Macina disclosed (para 0201): “The invention also provides a method of staging colon cancer in a human patient. The method comprises identifying a human patient having colon cancer and analyzing cells, tissues or bodily fluids from such human patient for expression levels and/or structural alterations of one or more CaSNAs or CaSPs1. First, one or more tumors from a variety of patients are staged according to procedures well known in the art, and the expression levels of one or more CaSNAs or CaSPs is determined for each stage to obtain a standard expression level for each CaSNA and CaSP. Then, the CaSNA or CaSP expression levels of the CaSNA or CaSP are determined in a biological sample from a patient whose stage of cancer is not known. The CaSNA or CaSP expression levels from the patient are then compared to the standard expression level. By comparing the expression level of the CaSNAs and CaSPs from the patient to the standard expression levels, one may determine the stage of the tumor.”
One of the markers Macina disclosed for which over-expression correlated with a poor prognosis was SPP1 (para 0031, claim 11).
Macina disclosed that Lynch syndrome conferred an increased risk for developing colon cancer (para 0004).
Regarding claim 20, Macina disclosed that the marker could be detected in tissue (para 0034) and by immunohistochemistry (para 0173, 0185).
Regarding claims 25 and 34, Macina discussed the use of surgery with or without adjuvant therapy for treatment of stage II colon cancer (para 0013).
Agrawal demonstrated that osteopontin (another name for SPP1) was a “lead marker of colon cancer progression” (see title), demonstrating it to be increasingly expressed at both the mRNA and protein levels as cancer progressed; see, e.g., page 518, last full paragraph in left column and paragraph spanning columns, and Fig 5 and 6. Agrawal used immunohistochemistry on paraffin-embedded tissue for detection of the protein.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to use the method disclosed by Macina for detecting and staging colorectal cancer by detecting protein levels of SPP1 in tissue from a subject, and based on the staging, select appropriate treatment, since Macina disclosed that staging was used in making treatment decisions. In addition, using SPP1 solely as a means of detecting colon cancer (regardless of staging), would have prompted a physician to treat the patient. One would have been motivated to select SPP1 from the finite list of markers disclosed by Macina because Agrawal taught this marker to be a “leading marker of colon cancer progression”. Finally, it would have been obvious to test for this marker in patients with Lynch syndrome because Macina taught such patients were at increased risk of developing colon cancer.
Regarding claim 26, because Lynch syndrome is by definition a MMR-d condition, applying the method to cancer patients having Lynch syndrome would meet the limitations of claim 26 as well.
Claim(s) 17, 21 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Macina (US 2010/0009905) in view of Agrawal (Journal of the National Cancer Institute 94(7):513-521 (2002)) as applied to claims 1, 20, 25, 26 and 34 above, and further in view of Jakubowska (Oncology Letters 12:3591-3597 (2016)).
The teachings of Macina and Agrawal, have been discussed. Regarding claim 28, Macina disclosed that expression could be measured in primary tissue (para 0216, 0242).
Macina and Agrawal did not disclose calculating an H-score, or that the value of the H-score was greater than 100.
Jakubowska taught how to calculate an H-score as a way to derive a numerical result from immunohistochemical analysis and set cutoff considered positive as >150 (page 3592, right column, second full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to use the H-score method when assessing SPP1 levels when practicing the method suggested by the combined teachings of Macina and Agrawal, since this represents a known technique for quantifying the results of IHC analysis. Regarding claim 21, there would be no way for one practicing the method to force the results of a particular patient sample to have an H-score of greater than 100, or to know what the score of a particular patient sample would be prior to actually analyzing it. However, it would have been obvious to calculate an H-score when performing IHC analysis on a cancer patient tissue sample regardless of what the ultimate score turned out to be.
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Macina (US 2010/0009905) in view of Agrawal (Journal of the National Cancer Institute 94(7):513-521 (2002)) as applied to claims 1, 20, 25, 26 and 34 above, and further in view of Paiva (US 2020/0048709, previously cited).
The teachings of Macina and Agrawal have been discussed. These references did not discuss normalizing measured expression levels.
Paiva taught that normalizing “refers to a transformation of quantified gene expression levels to account for potential systematic bias and to permit accurate comparison of relevant differential expression levels” (paragraph 0057).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant application when practicing the method suggested by the combined teachings of Macina and Agrawal to normalize the measured expression levels of the biomarkers in order to account for potential systematic bias and to permit accurate comparison of relevant differential expression levels.
Response to Arguments
Applicant's arguments filed 07/06/2026 have been fully considered but they are not persuasive. Applicant argues:
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As to point (a), the current rejection is based on the teachings of Macina and Agrawal, and the reasoning as to why one would test for SPP1/osteopontin expression in Lynch syndrome patients is discussed therein. As to point (c), the rejection is based on the teachings of both Macina and Agrawal to detect SPP1/osteopontin expression in colon cancer patients, including those whose colon cancer resulted from accumulated mutations due to the deficient mismatch repair system seen in Lynch syndrome. Obviousness does not require the same reason as Applicant’s for selecting SPP1.
As to point (b), this appears to be based on Applicant’s later argument based on Eremo (item 2, page 8 of the reply). Firstly, Eremo is not relied upon for any current rejection. Secondly, Agrawal showed that both OPN RNA and protein levels in the tissue correlated with the progression of colorectal cancer, thus establishing a reasonable expectation of success for use of this marker to stage the cancer, and thereby select appropriate treatment.
Applicant also argues:
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This argument is not persuasive. Firstly, while SPP1 protein may be elevated in LS cancer tissue, Applicant does not demonstrate that it is “specifically” elevated in LS cancer tissue (i.e. “only” in LS cancer tissue). Secondly, LS leads to accumulation of mutations that result in cancer. Agrawal has shown that SPP1/OPN protein levels are increasingly elevated as colon cancer progresses, and there is no evidence of record that would suggest that colon cancer that resulted from mutations caused by LS would differ from colon cancer arising from those same mutations resulting from non-LS pathways. Therefore, there would have been a reasonable expectation of success that SPP1 protein would serve as a marker for progression of colon cancer in subjects having LS as well.
Conclusion
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 SAMUEL C WOOLWINE whose telephone number is (571)272-1144. The examiner can normally be reached 9am-5:30pm.
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/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
1 CaSP = Cancer specific polypeptide (para 0061).
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