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 .
Claim Status
Claims 1-3, 6-17, and 19-21 are pending. Claims 4-5 were canceled, and claims 1 and 7 were amended in the Reply filed 11/26/2025. Claims 2-3, 7-17, and 19-21 remain withdrawn1. Claims 1 and 6 are presently considered.
Power of Attorney Not of Record
The POA filed 11/12/2025 is acknowledged.
Election/Restrictions
Applicant’s election of Group I (original claims 1-17 and 19-20) and the species of (v) Example 15 administering the PKR inhibitor CAS 608512-97-6 to RPE cells at 25-200 nM (see, e.g., Reply filed 7/30/2025 at 1; see Requirement mailed 4/30/2025 at 3-4) in the reply filed on 7/30/2025 was previously 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Claims 21 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group II), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/30/2025.
The Examiner’s understanding of the originally elected species was placed on record in the previous action (see, e.g., Action mailed 8/28/2025 at pages 2-4). The originally elected species was understood to read upon claims 1 and 4-6 as filed 6/24/2022, but not upon claims 2-3, 7-17, and 19-21 as filed 6/24/2022 for reasons of record (see, e.g., Action mailed 8/28/2025 at pages 2-4). The originally elected species was previously deemed allowable (see, e.g., Action mailed 8/28/2025 at page 4 at 1st full ¶)2. However, Applicant failed to identify if the amended claims filed 11/26/2025 continues reading upon the originally elected species or not. Upon review, it is reasonably understood that the originally elected species of Example 15 is excluded from the amended claim scope at least because (i) Example 15 fails to identify any “assaying” or “selecting” step prior to the “contacting” step, (ii) Example 15 does not actually show treatment of neoplasia as recited at amended claim 1, and (iii) Example 15 lacks any contingent step limiting treatment to only some cells but not others (see, e.g., Reply filed 11/26/2025 at claim 1, Remarks at 8 at final two ¶¶, explaining that the claim includes a contingent step, wherein “As a second step, if the OFR2p expression levels in cells are found to be less than the ORF1p levels, then these cells are treated….”). Therefore, the amendments filed 11/26/2025 are understood to exclude the originally elected species.
Per MPEP § 803.02(III),
Should applicant, in response to a rejection of a Markush claim, overcome the rejection by amending the Markush claim to exclude the species anticipated or rendered obvious by the prior art, the amended Markush claim will be examined again. The examination will be extended to the extent necessary to determine patentability of the Markush claim. In the event prior art is found during this examination that anticipates or renders obvious the amended Markush claim, the claim will be rejected and the action can be made final
Accordingly, Examination has been extended to a non-elected species of newly amended claim 1, namely the species rendered obvious in view of WO 2017/143308, Henry et al3, US 10,214,591, and WO 2014/004945 A1, as applied below.
Per MPEP § 803.02(III), claims directed to other nonelected species remain withdrawn.
Claims 2-3, 7-17, or 19-20 are 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 7/30/2025.
Claims 1 and 6 are presently considered are presently considered.
Priority
Priority to US Provisional Application 62953743 (12/26/2019) is acknowledged.
However, Examiner notes the existence of differences between the instant Specification and the provisional exist (e.g., compare Pro’743 at ¶¶[0217]-[0219] with Spec. filed 6/24/2022 at ¶¶[0217]-[0219]4), and differences between the provisional and the instant claim set.
Information Disclosure Statement
No IDS was filed in the Reply submitted 11/26/2025.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action.
Claims 1 and 5 were previously understood to be representative of the pending claim scope. In the Reply filed 11/26/2025, claim 5 was canceled and claim 1 was amended5 as follows:
A method for treatment of a neoplasia in a cell or population of cells comprising: assaying the cell or population of cells to measure open reading frame 1 protein (ORF1p) and open reading frame 2 protein (ORF2p) expression;
Selecting the cell or population of cells having reduced expression of ORF2p relative to ORF1p expression,
contacting the cell or population of cells selected with one or more protein kinase RNA activated (PKR) targeting agents to the cell or cells, thereby increasing expression of ORF2p in the cell or population of cells and,
treating neoplasia the cell or population of cells.
Applicable claim interpretations are discussed below.
Regarding the preamble of claim 1 (“for treatment of a neoplasia in a cell…”), per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Here, the preamble of claim 1 is understood to recite an intended and expected result that is fully satisfied by prior art that satisfies the steps and structures recited in the body of the claim, namely any prior art method that results in “increasing expression of ORF2p in the cell” (see also MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”).
Amended claim 1 now recites and requires “treating neoplasia the cell or population” at the final line. The term “neoplasia” is undefined on record, but is generally defined in the art to mean “the abnormal, excessive, and uncontrolled proliferation of cells, forming a mass of tissue known as a neoplasm or tumor”; or “the formation of tumors” or “a tumorous condition”; or “tumor growth” or “the formation and growth of new tissue”. Accordingly, claim 1 is understood to require treatment of neoplasia.
“Treatment” is interpreted in view of the description provided in the specification (see, e.g., Spec. filed 6/24/2022 at ¶[0056]), and is therefore understood to include diagnostic and preventative care.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
“Dosage” is not presently recited in the claims, but the disclosure informs artisans of relevant concentrations (see, e.g., Spec. filed 6/24/2022 at ¶[0062]), and include administration of compounds “from about 1 nM to about 10,000 nM” (see id).
“Expression” is not defined on record, and is therefore given the broadest reasonable interpretation in view of the prior art to include both protein and nucleotide expression.
“PKR targeting agents” is interpreted in view of the description provided in the specification (see, e.g., Spec. filed 6/24/2022 at ¶¶[0047]-[0048]), and is understood to be fully satisfied by all compounds recited at dependent claim 6.
“PKR” is understood to be “protein kinase RNA activated” (see, e.g., Spec. filed 6/24/2022 at ¶¶[0010]-[0011]), which is “Protein Kinase R”, a serine-threonine kinase encoded by EIF2AK2 (see, e.g., Spec. filed 6/24/2022 at ¶[0044]).
“Contacting” is understood in view of the originally filed disclosure to broadly include any relevant administration routes (see, e.g., Spec. filed 6/24/2022 at ¶[0072]).
The originally elected PKR targeting agent is understood to be CAS 608512-97-66, which is understood to be known as “C16”, 6,8-Dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzothiazol-7-one, and other names7.
Regarding the clause stating “thereby increasing expression of ORF2p in the cell or population of cells and, treating neoplasia the cell or population of cells” at claim 1: Per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”. Here, the “wherein” clause does not unambiguously correspond to a clear structure/function relationship in the original disclosure, and therefore is not a functional limitation. Rather, the “wherein” clause is understood to merely recite an intended or expected result fully satisfied by the positively recited steps and/or structures set forth in the body of the claim. Therefore, the “thereby” or “wherein” clause is understood to be fully satisfied by all prior art embodiments that satisfy the positively recited step of “contacting” the cell(s) with one or more PKR targeting agents.
Additional claim interpretations are discussed in the rejections, below.
Claim Objections
Claim 1 is objected to because of the following informalities:
Amended claim 1 recites “treating neoplasia the cell or population of cells” which is grammatically incorrect. Presumably, claim 1 should recite “treating neoplasia within the cell or population of cells” or “treating neoplasia of the cell or population of cells”.
Appropriate correction is required.
Withdrawn Claim Rejections
The rejection of claim 1 under 35 U.S.C. 101 is withdrawn in view of the amendments to claim 1 as filed 11/26/2025.
The rejection of claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn as moot in view of the cancellation of claim 4.
The rejection of claim 1 under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by US 10,214,591 (Feb. 26, 2019; cited in previous action) is withdrawn in view of the amendments to claim 1 as submitted in the Reply filed 11/26/2025.
The rejection of claims 1 and 5-6 under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by Bat-Erdene et al.8 is withdrawn in view of the amendments to claim 1 and the cancellation of claim 5 as submitted in the Reply filed 11/26/2025.
The rejection of claims 1 and 5-6 under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by WO 2017/143308 (Aug. 24, 2017; cited in previous action) is withdrawn in view of the amendments to claim 1 and the cancellation of claim 5 as submitted in the Reply filed 11/26/2025.
The rejection of claims 1 and 5-6 under 35 U.S.C. 103 as being unpatentable over Bat-Erdene et al.9 as applied to claims 1 and 5-6 above, is withdrawn in view of the amendments to claim 1 and the cancellation of claim 5 as submitted in the Reply filed 11/26/2025.
The rejection of claims 1 and 5-6 under 35 U.S.C. 103 as being unpatentable over WO 2017/143308 (Aug. 24, 2017) as applied to claims 1 and 5-6 above, is withdrawn in view of the amendments to claim 1 and the cancellation of claim 5 as submitted in the Reply filed 11/26/2025.
The rejection of claims 1 and 4-6 under 35 U.S.C. 103 as being unpatentable over WO 2017/143308 (Aug. 24, 2017) as applied to claims 1 and 5-6 above, and further in view of Henry et al10, US 10,214,591 (Feb. 26, 2019), and WO 2014/004945 A1 (Jan. 3, 2014), is withdrawn in view of the amendments to claim 1 and the cancellation of claims 4-5 as submitted in the Reply filed 11/26/2025. A revised rejection using one or more of these references has been set forth below, as necessitated by Applicant’s amendments.
New Claim Rejections Necessitated by Applicant Amendment
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 6 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.
Amended claim 1 now recites and requires “selecting the cell or population of cells having reduced expression of ORF2p relative to ORF1p expression” as filed 11/26/2025, and this phrase renders the claim scope indefinite. As an initial matter, the term “having reduced expression” is understood to presume the existence of an unknown, unclaimed, and unspecified state from which a reduction in expression is actually determinable. This is pertinent because expression (both gene and protein expression) is art-recognized as a dynamic process that fluctuates over time; furthermore, the expression levels of both ORF2p and ORF1p vary with time, cell type, and health since both are art-recognized biomarkers11,12. Accordingly, it is unclear and ambiguous how a “reduced expression” is supposed to be determined in the absence of a pre-existing comparator from which a reduction is measured, which renders the claim scope indefinite. For purposes of applying prior art, amended claim 1 is understood to require “selecting the cell or population of cells wherein ORF2p expression is less than the ORF1p expression”. This interpretation is reasonable in view of the Applicant’s own explanation in the Reply that “As a second step, if the OFR2p expression levels in cells are found to be less than the ORF1p levels, then these cells are treated….” (see, e.g., Reply filed 11/26/2025 at 8 at final two ¶¶).
Amended claim 1 now recites and requires “selecting the cell or population of cells having reduced expression of ORF2p relative to ORF1p expression” as filed 11/26/2025, and this phrase renders the claim scope indefinite because it is unclear how “relative to” should be interpreted, and close prior art exists. Expression of one protein “relative to” another may be determined by
a comparison of absolute copy numbers (e.g., if there are 5 copies of ORF2p vs 100 copies of ORF1p within a single cell, then ORF1p is expressed at higher levels “relative to” ORF2p);
a comparison of expression relative to a unknown basal level of expression (e.g., 5 copies of ORF2p vs 100 copies of ORF1p, but wherein basal levels are typically 1 copy of ORF2p vs 200 copies of ORF1p; this would mean that ORF2p is being expressed at 500% basal levels but ORF1p is expressed at 50% of basal levels, and therefore ORF2 is expressed at higher levels “relative to” ORF1p).
Accordingly, the meaning of “relative to” may imply and be interpreted differently, which materially and substantially alters the scope of the instant claim. Furthermore, close prior art exists (see, e.g., Action mailed 8/28/2025 at 14-26, noting multiple references applied under 35 USC 102 or 103). Accordingly, close prior art exists and the metes and bounds of the claim are unknown, and may be interpreted in different and non-synonymous ways; therefore, amended claim 1 is rejected as indefinite. For purposes of applying prior art, amended claim 1 is understood to require “selecting the cell or population of cells wherein ORF2p expression is less than the ORF1p expression”. This interpretation is reasonable in view of the Applicant’s own explanation in the Reply that “As a second step, if the OFR2p expression levels in cells are found to be less than the ORF1p levels, then these cells are treated….” (see, e.g., Reply filed 11/26/2025 at 8 at final two ¶¶).
Amended claim 1 is indefinite because it is unclear if the “contacting” step (and “treating”) are intended to be contingent limitations or not, because it is unclear how “reduced expression” is determined as explained above. This issue is easily illustrated by noting that the amended claim reads upon assays and selections involving a single cell (see, e.g., instant claim 1, reciting “A method for treatment … in a cell… comprising: assaying the cell…. to measure [ORF1p] and [ORF2p] expression; selecting the cell . . . having reduced expression…”). Accordingly, if the single cell is assayed but is not found to have “reduced expression”, presumably it cannot be “selected”, and therefore the “contacting” (and treating) step is presumably never reached. This analysis may be extended to an entire “population” of identical cells, which may be assayed, but if no cell is found to have “reduced expression”, presumably the population cannot be “selected”, and therefore no “contacting” (or “treating”) step occurs. If the “contacting” (and “treating”) step is contingent upon “selection”, then it is properly interpreted under MPEP § 2111.04(II) (see, e.g., MPEP § 2111.04(II), explaining contingent limitations, and noting that “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”). This would mean that claim 1 would be anticipated by prior art teaching the “assaying” step of claim 1 alone in a cell (or cells) wherein ORF2p expression is not “reduced” “relative to” ORF1p expression, since the remaining steps are contingent. However, if the “selecting” step requires “reduced expression” relative to unknown basal levels in an unknown comparator cell, then it is unclear whether or not (or under what specific conditions) the “contacting” step is contingent upon the selecting step. Stated alternatively, it is unclear if a single cell can ever be “not selected” at the “selecting” step, or if the analysis of expression requires a minimum of one cell to always be selected. Clarification is required, and if the “contacting” step is contingent upon selection, such contingency should be clearly and unambiguously identified in the claimed invention using a term such as “if” in a phrase such as “if ORF2p expression is less than the ORF1p expression, then subsequently treating the cells…”.
Claim 6 depends upon an ambiguous base claim, but fails to clarify the indefiniteness of the base claim. Accordingly, claim 6 is rejected for the reasons discussed above and applied to instant claim 1.
Claims 1 and 6 are rejected.
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.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/14330813 in view of Henry et al14, US 10,214,59115, and WO 2014/004945 A116.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding rejection and also in a separate section above, and those discussions and interpretations are incorporated into the instant rejection. Because claim 1 has been rejected as indefinite, the scope of the claim is understood to include at least methods wherein (i) Expression levels of ORF2p and ORF1p are assayed, and (ii) the cells are treated with a PKR targeting agent. This is reasonable because the claim scope is open-ended, and the “selecting” and “contacting” steps do no exclude the further selection and treatment of all assayed cells. Additional claim interpretations are set forth below.
Regarding instant claims 1, 6, and the treatment of cancer cells by administering a PKR, WO 2017/143308 teaches, discloses, and claims methods of administering C16 to treat any type of cancer (see, e.g., WO’308 at ¶[0010], claims 1, 4-5, 10, 13, 17, 21-22, and 25), wherein “C16” would be understood to be 6,8-Dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzothiazol-7-one (see, e.g., WO’308 at ¶[0079]; compare id. with instant claim 6; see also WO’308 at ¶¶[00126], [00131], [00138]-[00141]).
The teachings of the primary reference differ from amended claim 1 as follows: Although WO’308 discloses the administration of C16 to cancer cells, cancer cell populations, and patients having cancer, WO’308 is silent regarding the assessment of ORF1p and ORF2p expression levels in cells.
Accordingly, the relevant issue is whether or not it would have been obvious in view of the prior art to modify the cancer treatment methodologies of the primary reference by measuring ORF1p and ORF2p expression levels in a cell, population of cells, or in a patient before or during treatment with C16.
Biomarkers are commonly utilized in cancer fields for multiple reasons: Henry establishes that biomarkers are routinely utilized by artisans in the cancer treatment, cancer diagnosis, cancer screening, and cancer risk assessment arts (see, e.g., Henry at title, abs, Table 1 at 141, 141 at § 2 at col I to p. 142 at col I at final ¶, 144 at col II at § 8). Accordingly, an artisan would readily appreciate that a cancer biomarker may be utilized to (i) screen for cancer in patients, (ii) monitor progression of cancer, (iii) monitor for disease recurrence, and (iv) to monitor response to treatments (see, e.g., Henry at Table 1 on p. 141, 142 at col. I at 4th full ¶). Accordingly, the basic utility of biomarkers in the cancer arts was well-known in the prior art. Furthermore, Henry identifies the basic methodology for testing, evaluating, and confirming the utility of a biomarker for a particular type of cancer (see, e.g., Henry at 142 at col II at § 4 to p. 143 at col I at § 4.3 “Clinical Utility”). Accordingly, the measurement and utility of cancer biomarkers, as well as methods for assessment of clinical validity and utility were known in the prior art.
L1-ORF2p is an art-recognized biomarker for cancer: US’591 teaches and discloses that ORF2p can be advantageously assayed in tissue samples, including cancer tissues (see, e.g., US’519 at claims 6-8, 12-13, col. 26 at lines 10-62, col 28 at lines 7-35, col. 30 at lines 1-65, col. 31 at Table 1), wherein ORF2p is understood to be overexpressed in some cancer cells (see, e.g., US’519 at col. 3 at lines 29-33, col 14 at lines 5-45), and wherein detection and monitoring of ORF2p predictably permits artisans to detect and monitor the progression of cancer with high sensitivity (see, e.g., US’519 at col. 5 at lines 20-35, claims 6-8, 12-13). Accordingly, US’591 reasonably informs artisans that ORF2p is an art-recognized biomarker usable to monitor cancer progression and treatment (see, e.g., US’519 at claims 6-7). Accordingly, ORF2p is a prior art element, and measuring and detecting ORF2p overexpression was already known in the art for the purpose of detecting and monitoring the progression of cancer.
L1-ORF1p is an art-recognized biomarker for cancer: WO’945 discloses that ORF1p may be advantageously utilized as a biomarker for diagnosing and measuring the progression of cancer (see, e.g., WO’945 at title, abs, 2 at lines 28-33, p. 5 at line 33 to p. 6 at line 5, claims 1-5, 9-10, 13, 15-18). More specifically, WO’945 explicitly teaches that “elevated levels of ORF-1 protein relative to a normal control is indicative of cancer” (see, e.g., WO’945 at claims 1, 9 and 13, and 17), and that that ORF-1 may be measured “to determine risk of LINE-1 overexpression-linked cancer” in a patient (see, e.g., WO’945 at claims 1, 9 and 13, and 17).
Accordingly, in view of US’519 and WO’945, an artisan would be aware that both L1-ORF2p and L1-ORF1p were art-recognized biomarkers for use in the cancers arts (see discussions above). As disclosed by Henry, the usage of biomarkers was already known to desirably and predictably (i) screen for cancer in patients, (ii) monitor progression of cancer, (iii) monitor for disease recurrence, and (iv) to monitor response to treatments (see, e.g., Henry at Table 1 on p. 141, 142 at col. I at 4th full ¶). Accordingly, an artisan would predictably measure and monitor the levels of both L1-ORF2p and L1-ORF1p to screen for cancer, monitor progression of cancer, monitor patients for disease recurrence, and also to monitor the response to treatments.
Regarding amended claim 1 and “selecting the cell or population of cells having reduced expression of ORF2p relative to ORF1p expression”, this limitation has been rejected as indefinite above (see, e.g., discussion under 35 USC 112(b) rejection, above). For purposes of the instant rejection, it is noted that “L1-encoded ORF1p and ORF2p are detected in a variety of cancers” (see, e.g., US’519 at col. 2 at lines 35-40), that both ORF1p and ORF2p are encoded by LINE-1 and expressed as bicistronic RNA (see, e.g., US’519 at col. 1 at lines 45-50), but US’519 further explains that ORF1 and ORF2 are “two different coding domains…exhibiting different localization, structure and biological function” (see, e.g., US’519 at col. 3 at lines 14-35). Accordingly, US’519 is understood to reasonably inform artisans that the expression levels of ORF1p and ORF2p are not correlated because “no connection between the levels of ORF1p and ORF2p expression was found” (see id). This is pertinent because it implies that ORF1p and ORF2p would have been predicted and expected to be expressed at different, non-correlated levels in cancer cells. Accordingly, ORF1p expression relative to ORF2p expression would be predicted and expected to vary in some cancer cells (and naturally), wherein one was expressed at a higher or lower level than the other. Although it is prima facie unknown what cancers do or do not express ORF12p at levels less than ORF2p, it would be obvious and routine to measure both known prior art biomarkers in patients and model systems of analytical and clinical validity for biomarkers as taught by Henry, which would necessarily and inherently result in the elucidation of such a relationship. As explained above, because increased expression of either ORF1 or ORF2 is indicative of cancer development or cancer risk, regardless of the which was expressed higher than the other, an artisan would readily appreciate that abnormally elevated levels of either were indicative of cancer development or cancer risk, and therefore appreciate that such cells or patients should be treated for cancer accordingly. Accordingly, the requirement does not appear to patentably differentiate the instant claims in a non-obvious manner relative to the prior art. In addition, or alternatively, claim 1 is open-ended and recites “comprising” language. Furthermore, amended claim 1 is silent regarding the treatment of cells having reduced expression of ORF1p relative to ORF2p expression. Accordingly, the instant claim does not exclude or prevent additional steps wherein simultaneous treatment is provided to cells having reduced expression of ORF1p relative to ORF2p expression. This is pertinent because simply following the teachings and guidance of the prior art would necessarily result in measuring both ORF1p and ORF2p expression, and treating all patients having either elevated ORF1p, elevated ORF2p, or both, identically, because all such patients would be in need of treatment for cancer.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason: The claimed invention is the obvious combination (or application) of prior art elements and techniques (e.g., the treatment method of cancer with C16 taught by the primary reference; the measurement of known biomarkers to screen cancer, monitor cancer, diagnose cancer, and monitor cancer treatments as taught by Henry, US’519, and WO’945), wherein the combination would improve the methodology of the primary reference in predictable and known ways, including permitting artisans to desirably modify the treatment of cancer with C16 in patients and cells, by also screening for cancer, monitoring cancer progression, diagnosing cancer, and monitoring the treatment of cancer using C16, exactly as taught and suggested in view of Henry, US’519, and WO’945 (see, e.g., MPEP §§ 2143(I)(A), (C), (D), and (G)). Furthermore, each element would merely perform its art-recognized function in combination as it does separately.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to follow the teachings of the prior art, but to optimize the concentration of a known compound for a known method (see, e.g., MPEP § 2144.05(II)(A)).
Accordingly, claims 1 and 6 are rejected.
Response to Arguments
Applicant's arguments filed 11/26/2026 have been fully considered but have been substantially rendered moot in view of the new or revised rejections necessitated by the Applicant’s amendments. Applicable arguments have been fully considered but not found persuasive as explained below.
As an initial matter, Examiner notes that Applicant’s characterization of the pending claim does not reflect the actual invention as presently claimed (see, e.g., Reply filed 11/26/2025 at 8 at penultimate ¶, reciting a claim having a clear contingent limitation).
Applicable arguments pertaining to the revised rejection under 35 USC 103 appears at pages 12-14 (see, e.g., Reply filed 11/26/2025 at 12 at final ¶ to page 14 at final ¶), and these arguments are considered below.
Arguments addressing references individually or otherwise addressing less than the combined teachings relied upon by the Examiner are not persuasive: It is the Examiner’s understanding that Applicant addresses the teachings of the references individually rather than in combination (see, e.g., Reply filed 11/26/2025 at 13 at 2nd ¶ alleging that WO’308 alone is “silent” regarding aspects of the invention; see id. at 13 at 2nd ¶ referring to Henry alone or only in combination with WO’308; see id. at 13 at 3rd ¶ alleging that Henry alone is “silent” regarding aspects of the invention; see id. at 13 at 3rd ¶ alleging that “Even if, one of skill in the art did combine these two references…”; see id. at 13 at 3rd ¶ incorporating arguments addressing US’591 alone; see id. at 13-14 at bridging ¶ referring to “the combination of WO’308, Henry and US’591”). In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The differences identified by Applicant are taught in view of the combination, not the individual references. Regarding arguments addressing combinations of references not relied upon by the Examiner, such arguments are moot because they do not address the merits of combined teachings of references actually relied upon by the Examiner.
References to unclaimed or unexamined limitations are not persuasive and fail to distinguish the claimed invention over the prior art of record: In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (see, e.g., Reply filed 11/26/2025 at 13 at 2nd ¶, referring to “doses”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
US’591 does not “teach away” from using a combination of the two biomarkers of ORF2p and ORF1p: It is the Examiner’s understanding that Applicant concludes that US’591 “focusses on ORF2p and refutes any involvement of ORF1p” and that “US’591 clearly teaches away from the Applicant’s invention” (see, e.g., Reply filed 11/26/2025 at 13 at 3rd ¶ to page 14 at 1st full ¶), wherein the basis for the Applicant’s position is understood to be the disclosure of US’591 quoted at page 13 (see, e.g., Reply filed 11/26/2025 at 13 at 3rd ¶). This is not persuasive because none of prior art references at issue “teach away” from the claimed invention since they do not actually “criticize, discredit, or otherwise discourage the solution claimed” (see, e.g., MPEP § 2141.02(VI)), namely the usage of two distinct biomarkers, individually taught and disclosed by the prior art, both of which are taught for use in the identification and risk of cancers in patients. Notably, the disclosure of US’591 quoted by Applicant instead exemplifies that one of skill in the art would readily appreciate that ORF1p and ORF2p should both be monitored and assayed, because they are not surrogates for one another. Notably, US’591 informs artisans that LINE-1 expresses two proteins (i.e., L1-ORF1 and LI-ORF2) (see, e.g., US’591 at col. 1 at lines 35-55), and that generally increased expression of LINE-1 was correlated to “aggressive neoplasms” (see, e.g., US’591 at col. 2 at lines 60-67). As explained in the rejection above, the increased expression of L1-ORF1p and L1-ORF2p are each independently taught and disclosed as indicative of cancers (see, e.g., WO’945 at claims 1, 9, 13, and 17; see, e.g., US’591 at claims 6-8, 12-13, col. 26 at lines 10-62, col 28 at lines 7-35, col. 30 at lines 1-65, col. 31 at Table 1). Therefore, because US’591 informs artisans that protein expression levels of ORF1p and ORF2p are not correlated, an artisan would readily appreciate that each biomarker predictably and desirably provides non-overlapping information regarding cancer risk (see, e.g., US’591 at col. 3 at 15-26). Accordingly, the art does not “teach away” from measuring both art-recognized biomarkers, but instead further supports that individually measuring both would be obvious, wherein elevated expression of either would be indicative of cancer development and risk. In sum, at no point does US’591 teach, disclose, or suggest that ORF2p could not be simultaneously monitored and screened with ORF1p. Accordingly, Applicant has not identified any disclosure that “criticizes, discredits, or otherwise discourages the solution claimed”. Therefore, all arguments and assertions premised upon a “teaching away” have been fully considered but not found persuasive.
Applicant recites case law but fails to provide an analysis of the facts of those cases to the instant case: It is the Examiner’s understanding that Applicant cites and quotes portions of Bausch & Lomb and In re Wright at page 14 (see, e.g., Reply filed 11/26/2025 at 14 at 1st partial ¶). These cases and the holdings therein are neither disputed nor dispositive of non-obviousness. Notably, Applicant fails to provide any explicit example of any explicit disclosure relied upon by the Examiner improperly; therefore, such references are not germane in the absence of missing explanations that Applicant failed to provide. Rather, the Examiner’s basis for determining obviousness relies only upon the teachings of the prior art, wherein the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including (i) methods of measuring ORF1p, (ii) methods of measuring ORF2p, and (iii) methods of treating cancers by administering the compound of C16. Accordingly, such arguments are not persuasive.
At page 14, it is the Examiner’s understanding that Applicant alleges
However, the Office cites the WO '945 application to assert that ORF1p expression relative to ORF2p expression would be predicted and expected to vary in some cancer cells (and naturally), wherein one was expressed at a higher or lower level than the other." See, Office Action, pg. 24-25. Applicant submits that the Office is speculating since the combination of references fail to disclose or even suggest that the ORF1p and ORF2p expression levels are utilized in identifying and treating a cancer cell, especially in view of the US'591 patent.
First, it is unclear exactly what Applicant is alleging that “the Office is speculating” about. If Applicant is referring to the assertion that “ORF1p and ORF2p would have been predicted and expected to be expressed at different, non-correlated levels in cancer cells” in the rejection, then this is supported by the citation to US’519 provided within the same section, which identifies that ORF1 and ORF2 are “two different coding domains…exhibiting different localization, structure and biological function”, and that the expression levels of ORF1p and ORF2p are not correlated because “no connection between the levels of ORF1p and ORF2p expression was found” (see, e.g., US’519 at col. 3 at lines 14-35). Accordingly, it is unclear what is being called “speculation” by the Applicant since such statements logically follow on the assumption that the prior art is fully enabled for what it discloses. Second, Applicant’s conclusory statement that “the combination of references fail to disclose or even suggest that ORF1p and ORF2p expression levels are utilized in identifying and treating a cancer cell” is unsupported by any objective evidence, but is instead contradicted by the cited disclosures of US’591 and US’945 set forth in the rejection. Each reference discloses one of the two proteins at issue, and informs artisans that if the individual proteins are expressed at an elevated level, it is indicative of cancer or cancer risk (see rejection, above). Accordingly, the Applicant’s statements are not persuasive because the usage of ORF1p and ORF2p were explicitly individually taught by the prior art, and the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)).
It is the Examiner’s understanding that Applicant is alleging that in their invention “inhibitors are administered after assaying the ORF1p and ORF2p expression levels” (see, e.g., Reply filed 11/26/2025 at 13 at 3rd ¶). This does not patentably distinguish the claimed invention over the prior art because, as explained in the rejection, Henry establishes that biomarkers are routinely utilized by artisans in the cancer treatment, cancer diagnosis, cancer screening, and cancer risk assessment arts (see, e.g., Henry at title, abs, Table 1 at 141, 141 at § 2 at col I to p. 142 at col I at final ¶, 144 at col II at § 8); therefore, an artisan would readily appreciate that cancer biomarkers may be screened and monitored before, during, or after treatment (see, e.g., id.; see also Henry at Table 1 on p. 141, 142 at col. I at 4th full ¶).
It is the Examiner’s understanding that Applicant is alleging that “The combination of references do not teach, disclose, suggest or otherwise provide any guidance to assay the ORF1p and ORF2p expression levels and if the ORF2p is less than the ORF1p expression level the inhibitor is administered” (see, e.g., Reply filed 11/26/2025 at 14 at 1st partial ¶). First, this description does not reflect the actual claimed invention, which does not recite a contingent limitation (“if”) and does not explicitly state “less than” (see id; see, e.g., Nystrom v. TREX Co., Inc., 424 F. 3d 1136, 1143 (Fed. Cir. 2005), explaining that "When different words or phrases are used in separate claims, a difference in meaning is presumed".). Accordingly, references to unclaimed limitations are not persuasive. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Second, the limitation regarding relative ORF1p and ORF2p are directly addressed and considered in the rejection, but Applicant has not addressed the explanation provided in the rejection. As noted in the rejection, if ORF1p is overexpressed or if ORF2p is overexpressed, an artisan would treat such cells (or patients) for cancer, regardless of which was expressed higher than the other. Alternatively, claim 1 is open-ended and recites “comprising” language, and amended claim 1 is silent regarding the treatment of cells having reduced expression of ORF1p relative to ORF2p expression. Accordingly, the instant claim does not exclude or prevent additional steps wherein simultaneous treatment is provided to cells having reduced expression of ORF1p relative to ORF2p expression. This is pertinent because simply following the teachings and guidance of the prior art would necessarily result in measuring both ORF1p and ORF2p expression, and treating all patients having either elevated ORF1p, elevated ORF2p, or both, identically, because all such patients would be in need of treatment for cancer. Accordingly, the limitations noted by the Applicant have been fully addressed on record, and Applicant failed to acknowledge, address, or rebut the explanation of record.
Allegations suggesting “skepticism of experts”: If Applicant means to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 as evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. The prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)), and no objective evidence rebutting this presumption has been placed on record to date.
Allegations suggesting “inoperability” or lack of enabling disclosure regarding a prior art reference: If Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. The Examiner’s position is that the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)). Accordingly, the Applicant has not satisfied their burden to rebut the presumption of operability of the prior art at this time (see, e.g., MPEP § 2121(I); MPEP § 716.07).
Applicant has a different rationale for arriving at the instant invention: If Applicant means to allege that Applicant had a different rationale for arriving at the claimed invention than relied upon by the Examiner to establish obviousness, Examiner notes that this is not persuasive because an examiner may support a determination of obviousness by relying upon a rationale that differs from the Applicant’s rationale (see, e.g., MPEP § 2144(IV)). Here, the Examiner’s rationales are explicitly identified in the rejection (i.e., MPEP §§ 2143(I)(A), (C), (D), and (G)), but Applicant fails to address or specifically dispute these rationales supporting a determination of obviousness. Accordingly, it is neither disputed nor dispositive of obviousness that the Examiner did not support a rationale that was not actually relied upon to establish prima facie obviousness.
Allegations suggesting “lack of predictability” or “lack of reasonable expectation of success”: It is the Examiner’s understanding that Applicant is alleging a lack of predictability or otherwise a lack of reasonable expectation of success (see, e.g., Reply filed 11/26/2025 at 13 at 3rd ¶ to 14 at 1st partial ¶). This is not persuasive. MPEP § 2143.02(II) explains that “[o]bviousness does not require absolute predictability”, but instead clarifies that only “at least some degree of predictability is required” (see, e.g., MPEP § 2143.02(II)). Here, the rejection explicitly addresses predictability and reasonable expectation of success, but Applicant fails to address the explicitly identified predicted and expected results set forth in the rejection. Here, the Examiner’s basis for “predictability” is merely based upon the presumption that the prior art is fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). As explained at MPEP § 2143.02, predictability and reasonable expectation of success are satisfied when “all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art”. Here zero evidence of unexpected results commensurate in scope with the requirements of MPEP 716.02 have been set forth on record, all elements of the claimed invention were known in the prior art, one of ordinary skill was fully enabled to combine each component using routine methods in the biochemical arts per the guidance of the references, and the elements would have merely performed their art-recognized, respective functions (see Rejection, above). Accordingly, such arguments are not persuasive.
No evidence of unexpected results has been placed on record: To date, zero evidence of unexpected results sufficient to rebut prima facie obviousness and commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 has been placed on record. Rather, all elements of the claimed invention, including the biomarkers utilized to detect cancer or cancer risk, and the compound utilized to treat cancer were known in the prior art, and appear to perform only their predicted and expected functions, which weighs in favor of a determination of obviousness per MPEP § 716.02(c)(II).
Accordingly, all applicable arguments have been fully considered, but not found persuasive in view of the revised rejection above, wherein all revisions or new rejections were necessitated by Applicant’s amendments.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Ardeljan et al.17 informs artisans that LINE-1 was an art-recognized biomarker of neoplasia circa at least 2017 (see, e.g, Ardeljan at title, abs, Fig. 2 on 818).
Marchal et al. 18 pertains to the role of PKR activation in neurodegeneration and cancer (see, e.g., Marchal at title, abs, Fig. 1 on 1970).
Watanabe et al.19 discusses PKR as a potential therapeutic target in cancer treatments (see, e.g., Watanabe at title, abs, 921 at § 3).
Pataer et al.20 teaches that inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity (see, e.g., Pataer at title, abs, passim).
US20120010178A1 (cited in previous action) discloses methods of treating cells and patients with compounds including PKR inhibitor (CAS # 608512-97-6)21 (see, e.g., US’178 at title, abs, ¶[0647]).
US20160258955A1 (cited in previous action) pertains to LINE-1 and ORF2 protein (see, e.g., US’955 at title, abs, claims).
WO2017/172839 (Oct. 5, 2017; cited in previous action) discloses methods of treating subjects having increased levels of LINE-1 expression (see, e.g., WO’839 at title, abs, claims).
US 10,214,591 (Feb. 26, 2019; cited in previous action) explains that increases in L1-ORF2p expression naturally occur in cells during tumorigenesis and pre-neoplastic transitions (see, e.g., US’591 at title, abs, col I at lines 15-35, col. 2 at lines 51-67). US’591 further explains that L1-ORF2p expression is routinely increased in routine experiments required to study L1-ORF2p, such as wherein cells are transfected by an expression vector expressing human L1-ORF2p (see, e.g., US’591 at col. 4 at lines 1-20).
Bat-Erdene et al.22 discloses a method wherein PKR inhibitors, namely AP-2 and C16, are administered to Breast Cancer Cells (“BCCs”) (see, e.g., Bat-Erdene at abs, Fig. 3 on 5 showing 2-AP, 6 at col II at last 2 paragraphs, Fig. 4 on 7 showing C16 and 2-AP), and desirably and beneficially result in the complete prevention of secretion of APRIL proteins from neutrophils, which reduces breast cancer cell growth and progression (see, e.g., Bat-Erdene at abs, 2 at col I at final ¶ to col II at 1st full ¶, 8 at col I). Bat-Erdene identifies that C16 was administered at 1 µM (see, e.g., Bat-Erdene at Fig. 4 on 7) and that 2-AP was administered at 5 mM (see, e.g., Bat-Erdene at Fig. 3 on 5, Fig. 4 on 7). Accordingly, the administration of PKR inhibitors such as 2-AP and C16 to cells or populations of cells was known in the prior art.
WO 2017/143308 (Aug. 24, 2017; cited in previous action) discloses “C16”, which is identified as 6,8-Dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzothiazol-7-one (see, e.g., WO’308 at ¶[0079]), and reduced to practice methods wherein C16 is administered to cells (see, e.g., WO’308 at ¶¶[00126], [00138]-[00139]) and to U87 xenograft mice (see, e.g., WO’308 at ¶¶[00131], [00140]-[0141]). WO’308 also claims methods of administering C16 to treat any type of cancer (see, e.g., WO’308 at claims 1, 4-5, 10, 13, 17, 21-22, and 25).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new or revised 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 RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 In the Reply filed 11/26/2025, claim 17 is not correctly indicated as withdrawn. As noted in the Action mailed 8/28/2025, claim 17 is withdrawn and examination has not proceeded to claim 17 at this time.
2 The originally elected species has been deemed free of the prior art in view of the usage of the novel combination of the specific inhibitor of C16 (CAS # 608512-97-6) administered to Retinal Pigment Epithelium-1 cells that have a doxycycline (Dox) controlled LINE-1 expression construct (RPE) at 25-200 nM, wherein higher concentrations of C16 in RPE cells are identified as toxic (see, e.g., Spec. filed 6/24/2024 at Example 15 at ¶¶[0033], [0216]-[0217], Figure 13; see esp. id. at ¶[0033]). The novelty is understood to come from the combination of an RPE cell line modified to express LINE-1 and the treatment of such cells with C16 with a non-toxic range.
3 Henry et al., Cancer biomarkers. Mol Oncol. 2012 Apr;6(2):140-6. doi: 10.1016/j.molonc.2012.01.010. Epub 2012 Feb 6. PMID: 22356776; PMCID: PMC5528374; hereafter “Henry”.
4 This example pertains to disclosures provided for incorporation by reference; however, Applicant is directed to 37 C.F.R. 1.57(d).
5 The amendments filed 11/26/2025 failed to properly show the correct amendments relative to claim 1 as previously examined. Presumably this was a cut and paste error, wherein the language of claim 5 was not properly shown as newly added to instant claim 1.
6 A.k.a., 6,8-Dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzothiazol-7-one, or “imidazolo-oxindole PKR-specific Inhibitor, C16”.
7 National Center for Biotechnology Information (2025). PubChem Compound Summary for CID 6490494, Imidazolo-oxindole PKR inhibitor C16. Retrieved August 22, 2025 from https://pubchem.ncbi.nlm.nih.gov/compound/Imidazolo-oxindole-PKR-inhibitor-C16.
8 Bat-Erdene et al., Neutrophil TLR4 and PKR are targets of breast cancer cell glycosaminoglycans and effectors of glycosaminoglycan-induced APRIL secretion. Oncogenesis. 2018 Jun 15;7(6):45. doi: 10.1038/s41389-018-0058-2. PMID: 29904116; PMCID: PMC6002394; hereafter “Bat-Erdene”; cited in Requirement mailed 4/30/2025.
9 Bat-Erdene et al., Neutrophil TLR4 and PKR are targets of breast cancer cell glycosaminoglycans and effectors of glycosaminoglycan-induced APRIL secretion. Oncogenesis. 2018 Jun 15;7(6):45. doi: 10.1038/s41389-018-0058-2. PMID: 29904116; PMCID: PMC6002394; hereafter “Bat-Erdene”; cited in Requirement mailed 4/30/2025.
10 Henry et al., Cancer biomarkers. Mol Oncol. 2012 Apr;6(2):140-6. doi: 10.1016/j.molonc.2012.01.010. Epub 2012 Feb 6. PMID: 22356776; PMCID: PMC5528374; hereafter “Henry”.
11 See, e.g., US 10,214,591; cited in previous action; at claims 6-8, 12-13, col. 26 at lines 10-62, col 28 at lines 7-35, col. 30 at lines 1-65, col. 31 at Table 1, explaining that ORF2p can be advantageously assayed in tissue samples, including cancer tissues; see also US’519 at col. 3 at lines 29-33, col 14 at lines 5-45, wherein ORF2p is understood to be overexpressed in some cancer cells ; see also US’519 at col. 5 at lines 20-35, claims 6-8, 12-13, explaining that detection and monitoring of ORF2p predictably permits artisans to detect and monitor the progression of cancer with high sensitivity.
12 See, e.g., WO 2014/004945 A1; cited in previous action; at title, abs, 2 at lines 28-33, p. 5 at line 33 to p. 6 at line 5, claims 1-5, 9-10, 13, 15-18, explaining that ORF1p may be advantageously utilized as a biomarker for diagnosing and measuring the progression of cancer.
13 Cited in previous action.
14 Henry et al., Cancer biomarkers. Mol Oncol. 2012 Apr;6(2):140-6. doi: 10.1016/j.molonc.2012.01.010. Epub 2012 Feb 6. PMID: 22356776; PMCID: PMC5528374; hereafter “Henry”; cited in previous action.
15 Cited in previous action.
16 Cited in previous action.
17 Ardeljan et al., The Human Long Interspersed Element-1 Retrotransposon: An Emerging Biomarker of Neoplasia. Clin Chem. 2017 Apr;63(4):816-822. doi: 10.1373/clinchem.2016.257444. Epub 2017 Feb 10. PMID: 28188229; PMCID: PMC6177209; hereafter “Ardeljan2017”; cited in previous action.
18 Marchal et al., The impact of PKR activation: from neurodegeneration to cancer. FASEB J. 2014 May;28(5):1965-74. doi: 10.1096/fj.13-248294. Epub 2014 Feb 12. PMID: 24522206; hereafter “Marchal”; cited in previous action.
19 Watanabe T, Imamura T, Hiasa Y. Roles of protein kinase R in cancer: Potential as a therapeutic target. Cancer Sci. 2018 Apr;109(4):919-925. doi: 10.1111/cas.13551. Epub 2018 Mar 23. PMID: 29478262; PMCID: PMC5891186; hereafter “Watanabe”; cited in previous action.
20 Pataer et al., Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity. Cancer Biol Ther. 2009 Feb;8(3):245-52. doi: 10.4161/cbt.8.3.7386. Epub 2009 Feb 8. PMID: 19106640; PMCID: PMC2854203; hereafter “Pataer”; cited in previous action.
21 A.k.a., 6,8-Dihydro-8-(1H-imidazol-5-ylmethylene)-7H-pyrrolo[2,3-g]benzothiazol-7-one, or “imidazolo-oxindole PKR-specific Inhibitor, C16”.
22 Bat-Erdene et al., Neutrophil TLR4 and PKR are targets of breast cancer cell glycosaminoglycans and effectors of glycosaminoglycan-induced APRIL secretion. Oncogenesis. 2018 Jun 15;7(6):45. doi: 10.1038/s41389-018-0058-2. PMID: 29904116; PMCID: PMC6002394; hereafter “Bat-Erdene”; cited in Requirement mailed 4/30/2025.