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
Claims 1 and 16 have been amended as requested in the amendment filed on 9 February 2026. Following the amendment, claims 1-4, 6-16, 18-20 are pending in the instant application.
Claims 9-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions.
Claims 1-4, 6-8, 12-16, and 18-20 are under examination in the instant office action.
Claim Objections (New, Necessitated by Amendment)
Claims 1 and 16 are objected to because of the following informalities: The claims contain new abbreviations that are not spelled out upon their first appearance within the claims (ex. DPA-CY3 and MFI). Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) (New, Necessitated by Amendment; Maintained in part)
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 1-4, 6-8, 12-16, and 18-20 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.
As amended, independent Claims 1 and 16 have been amended to recite, “wherein the cancer characterized by high surface PS-expressing cancer comprises cells having an Annexin V fluorescence of greater than or equal to about 2000 MFI”. This new limitation is directed to a functional limitation that fails to impose any structural or methodological limitations upon the scope of the claims. A functional limitation can provide a patentable distinction (limit the claim scope) by imposing limits on the function of a structure, material or action. Here, there are no such limits, thus the scope of the recitation is indefinite. Claims 1 and 16 attempt to limit the cancer by stating the cancer cells have an Annexin V fluorescence greater than or equal to about 2000 Mean Fluorescence Intensity (MFI). However, there are no positively stated active method steps whereby cells from the cancer are assessed for Annexin V fluorescence. Without recitation of such steps, the new limitation will be interpreted as merely reciting an inherent feature of all cancer cells that are characterized by high surface PS expression. MPEP 2173.05(g) states: “the use of functional language in a claim may fail ‘to provide a clear-cut indication of the scope of the subject matter embraced by the claim' and thus be indefinite.” It further states: “Examiners should consider the following factors when examining claims that contain functional language to determine whether the language is ambiguous: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim” (emphasis added). Here, the recitation renders unclear the scope of what is required for direct infringement, since method steps are implied but not positively stated. Since the claims fail to meet all (3) criteria set forth in MPEP 2173.05(g), then Claims 1 and 16 are rejected, and this affects the scope of all depending claims - 2-4, 6-8, 12-15, and 18-20.
Claim 12 stands as being indefinite for reasons of record. There are no methods steps that distinguish this claim over the scope of claim 8 and it is unclear whether or not direct infringement of this claim requires assessing that there is py-Hsp70 inactivation. Absent active method steps, this claim will be interpreted as merely reciting an inherent property – inactivation of py-Hsp70 – of the inhibitor of the parent claim, claim 8.
Claim Rejections - 35 USC § 101 (Maintained)
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
As currently amended, the rejection of Claims 1-8 and 12-22 under 35 U.S.C. 101 as being directed to a law of nature (natural phenomenon) and/or abstract idea judicial exception without significantly more, is maintained for reasons of record in the previous Office action.
On page 6 of Remarks filed 9 February 2026, Applicant traverses the rejection on the following ground. Applicant states: “The Office's position is that the recitation of ‘administering an anti- cancer therapy targeted to high surface PS expressing-cancers to the diagnosed subject,’ does not amount to a particular treatment. Without acceding to the merits of the rejection, the Applicant submits, by the amendments submitted herewith, the claims recite specific treatments. For at least these reasons, Applicant respectfully requests reconsideration and withdrawal of the rejection of the claims under 35 U.S.C. § 101.”
While this argument has been reviewed in full, it is not persuasive to overcome the rejections of record because the treatment step is still conditional upon detecting a presence of cancer-secreted soluble Hsp-70 in the liquid biological sample. Thus, treating is contingent upon certain conditions being met. MPEP 2111.04 (II) states: “The broadest reasonable interpretation [BRI] 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. For example, assume a method claim requires step A if a first condition happens and step B if a second condition happens. If the claimed invention may be practiced without either the first or second condition happening, then neither step A or B is required by the broadest reasonable interpretation of the claim. If the claimed invention requires the first condition to occur, then the broadest reasonable interpretation of the claim requires step A. If the claimed invention requires both the first and second conditions to occur, then the broadest reasonable interpretation of the claim requires both steps A and B.” Thus, the BRI of the claim is that the method requires obtaining a liquid biological sample and nothing more.
With respect to limitations reciting a “particular treatment” under Step 2A, Prong One, MPEP 2106.04(d)(2) states: “Examiners should keep in mind that in order to qualify as a ‘treatment’ or ‘prophylaxis’ limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition.” The BRI of instant claims does not affirmatively recite an action that effects treatment. In other words, no treatment is given if the presence of cancer-secreted soluble phosphorylated Heat shock protein-70 (Hsp70) in the liquid biological sample is NOT detected. Therefore, the claim fails to integrate the judicial exceptions into any practical application.
For all of these reasons, Claims 1-8 and 12-22 stand as directed to the judicial exception without significantly more.
Claim Rejections - 35 USC § 112(a) (Maintained)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
As currently amended, Claims 16 and 18-20 stand as rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, for reasons of record in the previous Office action.
On page 7 of Remarks (Id), Applicant traverses the rejection stating, “Applicant respectfully disagrees and traverses this rejection. Without acceding to the merits of the rejection, and in the interest of expediting prosecution, the Applicant submits this rejection is overcome by the amendment of the claims to recite "obtaining a baseline measurement of py- Hsp70" as shown in the claim amendments submitted herewith. Applicant respectfully submits that a person of ordinary skill in the art would recognize that unchanged py-Hsp70 levels after beginning treatment are indicative of ineffective treatments, and thus modulating the treatment is within the scope of skill in the art. For at least these reasons, Applicant respectfully requests reconsideration and withdrawal of the rejection of the claims under 35 U.S.C. § 112(a).”
While t his argument has been considered in full, it is not persuasive to overcome the rejection of record. Independent claim 16 has been amended to recite obtaining a baseline measurement of cancer-secreted soluble tyrosine-phosphorylated Hsp70 (py-Hsp70) in a liquid biological sample from the subject prior to commencing therapy; treating the subject with an anti-cancer therapy targeted to high surface PS expressing- cancers, wherein the anti-cancer therapy targeted to high surface PS expressing-cancers is selected from the group consisting of bavituximab, Saposin C-dioleoylphosphatidylserine (SapC-DOPS), phosphatidylcholine-stearylamine (PC-SA), DPA-CY3 1-palmitoyl-2-oleoyl-sn-glycero-3- phosphocholine (DPA-CY3/POPC), Chalepin, human annexin-V, PGN634, mchlN11, PPS1, PPS1D1, PSBP-6, hexapeptide E3, TSR-022, MBG543, BMS-986258, LY3321367, Sitravatinib,R428, TP0903, BMS-777607, NPS1034, MRX-2843, UNC2025, UNC3133, ONO-7475, Tyro3 inhibitors, 5F9, and combinations thereof; measuring a level of cancer-secreted py-Hsp70 in a liquid biological sample obtained from the subject after administering the anti- cancer therapy; and altering dosage of the anti-cancer therapy, frequency of dosing the anti-cancer therapy, or course of therapy administered to the subject based on the level of cancer-secreted soluble py- Hsp70 relative to the baseline measurement; wherein the cancer characterized by high surface PS-expressing cancer comprises cells having an Annexin V fluorescence of greater than or equal to about 2000 MFI.
The specification as filed fails to provide any guidance or direction for altering dosage of the anti-cancer therapy, frequency of dosing the anti-cancer therapy, or course of therapy administered to the subject based on the level of cancer-secreted soluble py- Hsp70 relative to the baseline measurement. The disclosure only teaches methods comprising identifying cancer secreted py-Hsp70 as a causal factor required for macrophage differentiation (pg. 28, Example 3); and that high surface PS on cancer cells also promotes macrophage differentiation and PS is known to bind Hsp70. The specification as filed provides no guidance pertaining to a correlation between the level of cancer-secreted soluble tyrosine-phosphorylated Hsp70 in a liquid biological sample and therapeutic efficacy of a cancer treatment. There was nothing in the art before the effective filing date of the application that overcame the lack of guidance in the disclosure as filed. Therefore, the examiner maintains the position that the instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and use the invention with a reasonable expectation of successfully monitoring therapeutic efficacy. A person having ordinary skill in the art would have to perform multiple further in vivo experiments, either in human clinical trials or in animal models that are predictive of treating high PS expressing cancers in order to demonstrate use of the invention with a reasonable expectation of success. Specifically, a skilled artisan would have to quantify the levels of cancer-secreted soluble tyrosine-phosphorylated Hsp70 in a liquid biological samples before and after treatment, and correlate beneficial therapeutic efficacy to a level of cancer-secreted soluble tyrosine-phosphorylated Hsp70 in a liquid biological sample. The amount of experimentation required for this enabling guidance, goes beyond what is considered ‘routine’ within the art, and constitutes undue further experimentation.
Therefore, Claims 16 and 18-20 stand as rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Claim Rejections - 35 USC § 103 (New, Necessitated by Amendment)
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
As currently amended, Claim(s) 1-2, 4-8, and 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Graf et al., 2018; taken with Lim et al., 2004; and Zhao et al. (2015) (all cited in the previous action).
On pages 7 of Remarks (Id), Applicant traverses the rejection based on Graf and Lim on the following grounds.
Applicant submits the rejection based upon Graf and Lim references is overcome by the amendment of the claims to recite the limitations of Claim 5 (pg. 7, last line)
In that same response, Applicant goes on to traverse the rejection based on Graf, Lim and Zhao on the following grounds.
Applicant argues, “Even if the person of ordinary skill would be motivated to combine features …none of the references provides a reasonable expectation of success in doing so” (pg. 8, last paragraph). Applicant asserts, “the mere fact that references can be combined does not render the resultant combination obvious unless results would have been predictable” (pg. 9, second and third paragraphs).
In contrast to the prior art, Applicant asserts the application describes a variety of findings that identify that intracellular Hsp70 lacked detectable tyrosine phosphorylation, while cancer-secreted Hsp70 was specifically tyrosine phosphorylated. The working examples report that essentially all secreted Hsp70 was phosphorylated (pg. 9, second to last paragraph).
Further, Applicant argues the disclosure demonstrates that cancer-secreted py-Hsp70 interacts with macrophage TLR2, drives MerTK upregulation, and produces anti-inflammatory M2 polarization even though most TLR receptors are “pro-inflammatory”. The specification ties this pathway to tumor growth and demonstrate “reduced tumor growth under Hsp70 knockdown or in TLR-null settings” (pg. 9, last two paragraphs). In addition, Applicant asserts, the application describes high-PS cancer cell lines report higher levels of secreted py-Hsp70 and there is a strong correlation between PS expression and Hsp70 secretion (pg. 10, first full paragraph).Thus, py-Hsp70 is a specific biomarker for high-surface PS cancers without biopsy.
Each of Applicant’s arguments will be addressed in turn below.
The amendment to the claims, rolling the limitations of Claim 5 into the base claim, does not overcome the rejection but merely necessitates the application of new art for those amended claims.
The prior art fully disclose detecting the presence of serum Hsp70 levels as correlating with the stage of cancer and in particular colorectal cancer which the instant claims define as a “high surface PS expressing cancer” (see instant claims 1 and 4; and, Graf pg. 543, Discussion, at bullet 4). The Graf et al. prior art further discloses Hsp70 inhibitors predictably treat cancer. Lim is only relied upon as teaching tyrosine phosphorylated Hsp70, in particular is a key feature of cancer. Each element is merely performing the same function as disclosed in the separate references. Where the prior art teaches a finite limit of identifiable solutions, a person having ordinary skill would have been able to pursue the known options according to known methods. Here, the prior art disclose only two finite options for soluble heat shock protein 70: Hsp-70 alone or phosphorylated-Hsp70. A person having ordinary skill would have been able to use the anti-phospho antibodies, as taught by Lim, in the methods of Graf with predictable success in identifying whether the Hsp70 that Graf teaches is or is not phosphorylated. In KSR the court stated, if this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (KSR International Co. v. Teleflex, Inc. 127 S. Ct. 1727, 82 USPQ2d 1385, Supreme Court, April 30, 2007). Applicant does not question that there is explicit motivation to combine, namely that Lim demonstrate Hsp70 is phosphorylated in cancer samples, only that the combination is not predictable. But it would have been well-within the technical grasp to exchange one antibody for another according to known methods, and a skilled artisan would have been able to use this substitution to predictably detect Hsp70, and particular the amount of secreted Hsp70 that was phosphorylated in cancer samples.
While Applicant asserts the instant application identified that intracellular Hsp70 lacked detectable tyrosine phosphorylation, while cancer-secreted Hsp70 was specifically tyrosine phosphorylated and report that essentially all secreted Hsp70 was phosphorylated. This is not persuasive to overcome the rejection because Graf a specifically focuses on secreted Hsp70 and cancer stage, and Lim demonstrate that phosphoproteins as a whole are relevant to metastasis and cancer stage.
Lastly, while Applicant asserts the Application has demonstrated a new mechanism of action, the interaction between py-Hsp70 with macrophage TLR2, that drives MerTK upregulation, and produces anti-inflammatory M2 polarization are all not features are recited within the instant claims. The court in Merck KGaA v. Integra LifeSciences Ltd, 50 USPQ2d 1846 (DC SCalif, 1999) held that a reference teaching a process may anticipate claims drawn to a method comprising the same process steps, despite the recitation of a different intended use in the preamble or the later discover of a particular property of an element used in the process. The case law applies to the instant claims because while the Graf prior art teaches secreted Hsp-70 is related to cancer staging, and Lim demonstrate Hsp70 is one of the phosphorylated proteins in cancer, the mechanism whereby py-Hsp70 specifically interacts with the immune system is not a salient feature of the instant claims. Nonetheless, Graf does outline a mechanism whereby Hsp70 interacts with immune cells in the cancer tumor environment (paragraph bridging pages 544-545 and first two paragraphs of pg. 545).
For all of these reasons, the examiner maintains that the invention of the claims is obvious in view of the combined teachings of the prior art references, and through what could have been achieved through routine experimentation of these methods.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STACEY NEE MACFARLANE whose telephone number is (571)270-3057. The examiner can normally be reached M-F 7:30-5 (EST) & Sat. A.M..
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/STACEY N MACFARLANE/Examiner, Art Unit 1675
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