FINAL ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Amendment and Response filed 10 March 2026. Claims 1, 3-5, and 7 have been amended, claims 8-9 and 13-14 have been canceled, and claims 17-22 have been added. Claims 4, 11, and 16 remain withdrawn (see also paragraphs 5-8 below), and claims 1-3, 5-7, 10, 12, 15, and 17-22 are under consideration herein. Applicant’s amendments and arguments have been thoroughly reviewed, and have overcome the following objections/rejections set forth in the prior Office action:
The objections to claim 1 and claims dependent therefrom, in view of Applicant’s corrective amendment;
The rejections of claims under 35 USC 112(b)(indefiniteness), in view of Applicant’s clarifying amendments (although it is noted that the claims remain rejected under 35 USC 112(b) for the reasons given below);
The rejection of claims under 35 USC 112(a) new matter, in view of the amendment of the claims to delete the recitation of “protein-code destructive mutations”; and
The rejection of claims under 35 USC 103, in view of Applicant’s amendments (particularly the amendment of the claims to recite “detecting a biallelic truncating mutation” as set forth in independent claims 1 and 5)(although it is noted that the claims remain rejected under 35 USC 103 for the reasons given below).
Claims 1-3, 5-7, 10, 12, 15, and 17-22 remain/are rejected for the reasons given below, which include new grounds of rejection necessitated by Applicant’s amendment.
Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 11/25/2024 is again acknowledged.
Claim 4 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/25/2024.
Applicant’s election of the species of PIGR in the reply filed on 11/25/2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 11 and 16 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/25/2024.
Claim Rejections - 35 USC § 112(b)/second paragraph
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claims 1-3, 5-7, 10, 12, 15, and 17-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-3, 15, and 17-19 are indefinite over the recitation in independent claim 1 of the limitation “detecting a biallelic truncating mutation”, as it is unclear whether the claim does or does not require an action/step sufficient to detect that at least one of a nonsense mutation, a frameshift mutation, and a “mutation at a splicing site” is present. Claim 1 recites the further limitation “wherein the biallelic truncating mutation comprises a nonsense mutation, a frameshift mutation, or a mutation at a splicing site”, suggesting the need to establish the presence of the underlying cause of the detected “biallelic truncating mutation”. However the specification at, e.g., pages 8-10 teaches a “truncating mutation” as an example of a loss-of-function mutation (with examples of truncating mutations being further taught as a nonsense mutation, frameshift mutation, and mutation at a splicing site; see page 8), and states that a loss-of-function mutation is one in which functional protein “is not expressed” (page 9), which mutation may be detected by carrying out immunostaining in which protein expression is “not observed” (page 9-10). Further, an example of such detecting is provided at, e.g., page 22, when the absence of detected PIGR protein expression as determined via immunostaining “was conceived to be due to the truncating mutation in the PIGR gene”, which is consistent with an embodiment set forth in dependent claim 3, which states “wherein the detecting the biallelic mutation….is carried out by immunostaining”, (suggesting that the claims may encompass methods in which a presence of a truncating mutation meeting the requirements of the independent claim is detecting by concluding/“conceiving of” such presence based on the absence of immunostained protein [as opposed to, e.g., a requirement to determine a specific, underlying cause of such truncating mutation]). As there are multiple reasonable interpretations of the claim language that impart different boundaries on what is claimed, further clarification is required.
Claims 5-7, 10, 12, and 20-22 are indefinite over the recitation in independent claim 5 of the limitation “detecting a biallelic truncating mutation”, as it is unclear whether the claim does or does not require an action/step sufficient to detect that at least one of a nonsense mutation, a frameshift mutation, and a “mutation at a splicing site” is present. Claim 5 recites the further limitation “wherein the biallelic truncating mutation comprises a nonsense mutation, a frameshift mutation, or a mutation at a splicing site”, suggesting the need to establish the presence of the underlying cause of the detected “biallelic truncating mutation”. However the specification at, e.g., pages 8-10 teaches a “truncating mutation” as an example of a loss-of-function mutation (with examples of truncating mutations being further taught as a nonsense mutation, frameshift mutation, and mutation at a splicing site; see page 8), and states that a loss-of-function mutation is one in which functional protein “is not expressed” (page 9), which mutation may be detected by carrying out immunostaining in which protein expression is “not observed” (page 9-10). Further, an example of such detecting is provided at, e.g., page 22, when the absence of detected PIGR protein expression as determined via immunostaining “was conceived to be due to the truncating mutation in the PIGR gene”, which is consistent with an embodiment set forth in dependent claim 7, which states “wherein the detecting the biallelic mutation….is carried out by immunostaining” (suggesting that the claims may encompass methods in which a presence of a truncating mutation meeting the requirements of the independent claim is detecting by concluding/“conceiving of” such presence based on the absence of immunostained protein [as opposed to, e.g., a requirement to determine a specific, underlying cause of such truncating mutation]). As there are multiple reasonable interpretations of the claim language that impart different boundaries on what is claimed, further clarification is required.
Claim Rejections - 35 USC § 103
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANT’S AMENDMENTS:
Claim(s) 1-3, 5-7, 10, 12, 15, and 17-22 are rejected under 35 U.S.C. 103 as being unpatentable over Traicoff et al (J. Biomed. Sci. 10:792-804 [2003]; previously cited) in view of Krajci et al (British Journal of Cancer 73:1503-1510 [1996]; cited herein), Stintzing (FIOOOPrime Reports 6:103 [2014]; previously cited), and Johansen et al (Mucosal Immunology 4(6):698 [Nov 2011]; previously cited).
Traicoff et al disclose characterization of PIGR expression in association with “colon tumorigenesis”, reporting that human PIGR mRNA “was found to be highly expressed in normal colon epithelium, but was decreased in 6 of 8 colon tumors”; see entire reference, particularly the Abstract, page 797 under the heading “PIGR Expression Is Decreased in Colon Tumors”, and Figure 2B. It is noted that while Traicoff et al refer to 6 of 8 colon tumor samples as exhibiting “reduced” expression of PIGR relative to matched normal colon tissue, based on Figure 2B itself, multiple such “reduced” samples exhibited no visible/detectable PIGR RNA. Traicoff et al teach that some of their findings suggest the possibility that alternative RNA splicing or a stop codon mutation may be causative of the observed aberrant PIGR expression (see page 801, top of left column and page 803), and Traicoff et al also teach that “Previous studies have demonstrated the utility of decreased PIGR expression as a prognostic variable in colorectal cancer”, referencing several other studies, including that of Krajci et al (see page 802, left column, final paragraph, and cite 24).
Krajci et al disclose measuring both secretory component (SC) mRNA and protein in both colorectal adenomas and colorectal carcinomas (see entire reference, particularly the Abstract); it is noted that Krajci et al teach that SC is encoded by PIGR (see, e.g., the Abstract and page 1508, right column, second full paragraph), and that the specification at, e.g., page 9, teaches that the secretory component (SC) “is a part of the PIGR protein” (see lines 18-19), such that Krajci et al’s disclosures regarding SC correspond to an expression product of PIGR. With regard to colorectal adenomas, Krajci et al report that “SC mRNA levels were positively related to SC protein expression; both mRNA and SC protein were negatively related to histological grade”, and that “SC mRNA levels tended to be related to the SC protein expression in the carcinomas” (Abstract); thus, Krajci et al show that both SC mRNA and SC protein may be measured as indicators of altered SC expression, and Krajci et al exemplify the use of immunostaining in measurement of SC protein (which again is a product of the PIGR gene) (see page 1506). Krajci et al state that “SC mRNA was detected in all adenomas, and only two of ten carcinomas (10.5%) deemed to be SC deficient by immunohistochemistry also lacked SC mRNA expression, suggesting diallelic alterations in the SC-encoding gene (locus PIGR)”, and Krajci et al further state that this finding “agreed with Southern blot analysis performed on a separate sample of 32 other colonic carcinomas” (Abstract, and see also pages 1508-1509). With further regard to this suggested loss of both alleles, Krajci et al suggest that these may result from frameshift or nonsense mutations or deletions affecting both PIGR alleles (see again page 1508, both columns). Thus, the teachings of Traicoff et al and Krajci et al establish that lost or reduced PIGR expression is associated with development of colorectal cancer, that both mRNA and protein may be measured as indicators of such loss, and that diallelic/biallelic truncating mutations (including frameshift and/or nonsense mutations as taught by Krajci et al) and/or mutations affecting splicing/splice sites (as taught by Traicoff et al) are all likely potential causes of such aberrant PIGR expression. Accordingly, in view of the teachings of Traicoff et al and Krajci et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have detected in a colorectal tissue sample (including, e.g., colon epithelium or tumors as taught by Traicoff et al and/or colorectal adenomas or carcinomas as taught by Krajci et al) any of decreased or absent PIGR/SC mRNA or protein, as well as any underlying cause of such aberrant expression - including a diallelic/biallelic truncating mutation and any cause thereof, encompassing a nonsense mutation and/or frameshift mutation and/or mutation at a splicing site – as an indicator of colorectal disease status/progression, possible CRC cancer prognosis, etc. (as suggested by both Traicoff et al and Krajci et al). An ordinary artisan would have been motivated to have performed such testing because Traicoff et al and Krajci et al teach that the emergence of such aberrant PIGR expression is associated with CRC cancer development and progression from benign disease to malignancy, etc.. Further, given the detailed guidance and materials disclosed by Traicoff et al and Krajci et al, an ordinary artisan would have had a reasonable expectation of success in performing such methods on colorectal tissues, tumor samples, etc.
While Traicoff et al teach that, e.g., colon neoplasia “progresses through distinct stages of hyperproliferative tissue, benign adenomas, and carcinomas of increasing aggressiveness” (page 792, right column), neither Traicoff et al nor Krajci et al teach performing such detecting on “an inflamed and non-cancerous region of a colorectal epithelial tissue sample”, as set forth in each of independent claims 1 and 5. Further, neither reference teaches an “administering” as set forth in claims 1 and 5.
With regard to the performance of detecting reduced/lost PIGR expression, including a biallelic truncating mutation in PIGR, in “an inflamed and non-cancerous region of a colorectal epithelial tissue”, as well as the administering of therapeutic agents as recited in the claims, Stintzing teaches that treatment options for colorectal cancer include, e.g., 5-fluorouracil, oxaliplatin, irinotecan, bevacizumab, cetuximab, panitumumab, and aflibercept (see entire reference); it is noted that the claims are directed to methods of “treating colorectal cancer” (see preambles of claims 1 and 5), and that Stintzing et al clearly teach such treatments. Based on the disclosure at paragraph 58 of the corresponding published application US 20220195534, several of the agents taught by Stintzing meet the requirements of the claims with regard to the types of therapeutic agents that may be employed in an “administering” meeting the requirements of the claims (including with regard to agents “for ulcerative colitis”). With regard to the limitation in each of the independent claims requiring performing the recited “detecting” on “an inflamed and non-cancerous region of a colorectal epithelial tissue sample”, Stintzing also disclose that inflammatory bowel diseases - including ulcerative colitis and Crohn’s disease - are known to increase risk for colorectal cancer “and warrant close surveillance programs” (page 1, right column). Johansen et al teach that rapid proliferation of “relatively undifferentiated epithelial cells” and downregulation of PIGR are common features of both colorectal tumors and intestinal epithelial cells (IECs) during inflammation associated with inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis (see entire reference, particularly page 600, right column first full paragraph, “Downregulation of pIgR expression in inflammatory bowel disease”). Thus, Stintzing et al teach an elevated risk of colorectal cancer (CRC) in subjects with IBD (including UC and Crohn’s) and suggest implementing “close surveillance programs” with respect to such subjects, while Johansen et al establish that decreased PIGR expression is a feature associated not just with CRC but with IBD/UC/Crohn’s, specifically in the environment of IECs during inflammation.
In view of the teachings of Stintzing and Johansen et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method suggested by Traicoff et al and Krajci et al so as to have performed such testing/detecting on “an inflamed and non-cancerous region of a colorectal epithelial tissue sample” – i.e., tissues of the type taught by Johansen et al - and to have administered to a subject exhibiting decreased/ absent PIGR expression, as well as a biallelic truncating mutation in PIGR, a therapeutic/ anticancer agent of the type taught by Stintzing, and thereby to have practiced methods meeting all requirements of the claims. An ordinary artisan would have been motivated to have made such a modification with regard to testing/detecting by both Stintzing’s teaching that such inflammatory conditions (including ulcerative colitis) increase risk for colorectal cancer and thus require added surveillance therefore, and Johansen et al’s teaching that PIGR downregulation is known to be associated not just with CRC but with inflammation in IBD/UC/Crohn’s (such that an ordinary artisan would have recognized this altered/absent expression and/or a biallelic truncating mutation in PIGR as a marker of inflammation/disease and need for treatment thereof, both with regard to CRC and IBD). Further, an ordinary artisan would have been motivated to have employed any of the known treatments taught by Stintzing as appropriate to treat the subject’s condition (whether it be CRC and/or IBD/UC/Crohn’s), simply for the benefit of alleviating the subject’s symptoms, successfully treating their condition, etc. Additionally and more generally, an ordinary artisan would have been motivated to have tested any inflamed colorectal epithelial sample from a subject (whether cancerous or non-cancerous) for the benefit of characterizing (with regard to PIGR expression/mutation or any other inflammation and/or cancer marker) the subject’s condition and treating it in an appropriate way (and it is noted that the current claim language embraces any type of “administering” of an agent of the type broadly set forth in the claims sufficient to achieve “treating colorectal cancer”, with the claims further encompassing [in view of the use of the transitional language “comprising”] any other needed additional testing of the subject). Further, in view of the guidance provided by the cited art with regard to the performance of testing and the administering of treatment, an ordinary artisan would have had a reasonable expectation of success in performing such methods.
With further regard to claims 2-3, 6-7, 10, 12, and 15, the limitations of each of these claims (which include PIGR and immunostaining thereof, as well as more preferred types of therapies) are discussed above. Regarding new claims 17-22, while it is again noted that it is unclear what the claims require with regard to the language “detecting a biallelic truncating mutation” (in independent claims 1 and 5, from which claims 17-19 and 20-22, respectively, depend), Traicoff et al and Krajci et al suggest detection of each of these mutations types, as indicated above.
It is noted that Applicant’s traversal of the prior rejection of claims under 35 USC 103 (Response of 10 March 2026) has been reviewed and considered to the extent that it may apply to the present rejection, but Applicant’s arguments are not found persuasive. It is particularly noted that the current rejection addresses the new claim limitation of “detecting a biallelic truncating mutation”, and that (particularly in view of Applicant’s amendments to the language dependent claims 3 and 7) the Kalady et al reference is no longer relied upon.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Agesen et al (Gut 61:1560-1567 [2012]; cited herein) teach a 13 -gene expression classifier for stage II CRC prognosis that includes PIGR (see entire reference). Jelinic et al (Nature Genetics 46(5):424 [2014]; cited herein) teach the use of massively parallel sequencing in detection of nonsense, frameshift, and splice-site mutations in SMARCA4 (see entire reference).
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 DIANA B JOHANNSEN whose telephone number is (571)272-0744. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm EST.
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
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