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 .
Information Disclosure Statement
The Information Disclosure Statement (IDS) filed on 03/29/2026 has been considered by the Examiner inasmuch as foreign documents have been submitted into the file wrapper in English.
Claim Status
Applicant’s arguments filed March 29, 2026 have been entered. Thus, claims 1-7, 10 and 17 are examined on the merits herein.
Priority
This application is a 371 of PCT/EP2019/086633 12/20/2019 which claims priority to EP 18214978.1 12/20/2018.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Arguments
(I) The rejection of claims 1-5, 10 and 17 under 35 U.S.C. 102(a)(1); and
(II) The rejection of claims 6-7 under 35 U.S.C. 103 are maintained.
Applicant argues:
(A) Prudent does not teach cancer inherently relates to the process of metastasis, i.e. the specific circulating tumor cells (CTCs) or CTC clusters in the bloodstream, see Applicant’s remarks, pg. 3 of 10, paragraph 3.
With respect to Applicant’s argument (A), the Examiner notes Prudent teaches cancer includes any number of diseases characterized by the ability of affected cells to spread through the bloodstream to other parts of the body (e.g. metastasize), as well as any of a number of characteristic structural and/or molecular features; and a cancerous cell or cancer cell is understood as a cell having specific structural properties which lack differentiation and are capable of invasion and metastasis; and exemplifies the cancer as breast cancer.
Prudent also teaches treating metastatic cancer which refers to treatment or prevention of cancer including any objective or subjective parameter such as abatement, and further includes the administration of an agent to inhibit development of the symptoms or conditions associated with a neoplastic disease, see Prudent, paragraph [0074].
(B) Prudent fails to disclose inhibition of metastasis in cancer and instead only discloses the treatment of primary and secondary tumors, see Applicant’s remarks, pg. 3 of 10, paragraph 4.
With respect to Applicant’s argument (B), the Examiner notes as evidenced by Aceto et al. (hereafter referred to as “Aceto-1”, Published 28 August 2014, Cell, Vol. 158, Issue 5, pp. 1110-1122, PTO-892), Aceto-1 discloses metastatic spread of breast cancer is typically to bone, lung, liver and brain, see pg. 1110, left column, introduction, paragraph 1.
Aceto-1 discloses epithelial mesenchymal transition (EMT) of individual cells within the primary tumor leads to their intravasation into the bloodstream, survival of such circulating tumor cells (CTCs) within the bloodstream, and finally their extravasation at distant sites have been demonstrated in human breast cancer cells in the circulation, see pg. 1110, right column, paragraph 1.
(C) Prudent entirely fails to teach the EDCs described therein are capable of inhibiting metastasis, in particular via the disruption of CTC clusters, since metastasis does not arise from in vitro cancer cell line cultures and because there is no secondary site to which cells can migrate, see Applicant’s remarks, pg. 3 of 10, last paragraph.
With respect to Applicant’s argument (C), the Examiner notes Prudent exemplifies EDCs that target CD147 and Na,K-ATPase in Example 3, see pg. 39, left column.
Prudent exemplifies the EDCs of EDC2.1, EDC2.2, EDC2.3 and EDC2.4 as useful in treating many types of cancer such as breast cancer reported in Example 8, see paragraph [0311]. Prudent reports that breast cancer cells which were CD147 positive had an EC50 of 0.45 nM against EDC 2.2 and an EC50 of 0.68 nM against EDC2.4, see pg. 41, Table 1.
Additionally, as evidenced by Kanwar et al. (Published 20 December 2014, International Journal of Cancer, Vol. 137, Issue 2, pp. 332-344, PTO-892), Kanwar discloses genomic signatures in circulating tumor cells from breast cancer, see pg. 332, title.
Kanwar discloses within Table 1 chromosomal regions within the signature of recurrent gains in circulating tumor cells (CTCs) were analyzed, and included the chromosomal region of 19p13 where the BSG gene was within the minimal common region (MCR), see pg. 338.
Kanwar discloses BSG is a tumor-aggressiveness related signature, see pg. 332, abstract; and that BSG (19p13.3) is also known as CD147, see pg. 339, left column, paragraph 2.
Kanwar discloses a study of single disseminated tumor cells in bone marrow from breast, prostate and lung cancer patients showing that mRNA and protein levels of BSG were elevated in 82% of cells examined, and thus BSG is an attractive candidate for a CTC specific marker, see pg. 339, left column, paragraph 2.
(D) In the absence of any explicit disclosure indicating that EDCs are effective in inhibiting metastasis, the Office’s rejection is reliant on hindsight and informed by the data provided by the present inventors, see Applicant’s remarks, pg. 3 of 10, last paragraph – pg. 4 of 10, first paragraph.
(E) Prudent entirely fails to recognize the significance of circulating tumor cells (CTCs), and more pertinently CTC clusters, in inhibition of metastasis in cancer, and consequently fails to recognize that disruption of these CTC clusters is important for effect and specific inhibition of metastasis, see Applicant’s remarks, pg. 4 of 10, paragraph 4.
(F) Prudent does not provide any teachings regarding the use of Na+/K+ ATPase inhibitors in the inhibition of metastasis and, in fact, does not specifically describe the inhibition of metastasis whatsoever, see Applicant’s remarks, pg. 5 of 10, last paragraph.
(G) Prudent fails to motivate the skilled person whatsoever to use the EDCs in the inhibition of metastasis in cancer in general; let alone in cancer characterized by the presence of CTC clusters, see Applicant’s remarks, pg. 5 of 10, last paragraph.
(H) Prudent provides no evidence that EDCs comprising an Na+/K+ ATPase inhibitor would be useful in inhibiting the distinct biological process of metastasis, i.e. via disrupting CTC clusters, and so treating metastasis in cancer, particularly characterized by the presence of CTC clusters, see Applicant’s remarks, pg. 6 of 10, paragraph 2.
With respect to Applicant’s arguments (D)-(H) and in view of the foregoing considerations, the Examiner notes there is particular reason to think the EDCs of Prudent, for example the EDCs comprising the agent which binds to CD147 as the targeting moiety and the agent that acts on Na,K-ATPase as the therapeutic agent would result in the inhibition of metastasis as argued by Applicant; particularly given the fact the EDCs of Prudent contain the agent which binds to CD147 as the target moiety and comprises the agent that acts on Na,K-ATPase as the therapeutic agent, for example the Na,K-ATPase inhibitor as taught by Prudent, and is further supported by Prudent demonstrating in Table 1 of Example 8 said EDCs have low nanomolar EC50 cytotoxicity against CD147-positive breast cancer cells; and further in view of the fact that it is known that CD147 is an attractive candidate for a CTC specific marker in breast cancer cells as disclosed by Kanwar.
Moreover, the Examiner notes within the prior art rejections below Aceto-2 discloses the identification of clusters of CTCs (CTC-clusters) in the circulation (e.g. bloodstream) of patients with cancer as demonstrated in breast cancer patient samples.
Furthermore, the Examiner notes instant claim 1 recites the disruption of circulating tumor cell (CTC) clusters as the mechanism of action for inhibiting metastasis in cancer by administering an effective amount of an Na+/K+ ATPase inhibitor as the therapeutic agent.
(I) Prudent teaches that the EDCs described therein do not have general anti-cancer activity but rather their effectiveness is dependent on cancer type and mutations present (see Example 8); and therefore, their effectiveness is highly dependent on specific factors which make their use complicated, see Applicant’s remarks, pg. 6 of 10, paragraph 3.
(J) The skilled person would be unlikely to consider the EDCs of Prudent due to their complexity and specificity of their use and probable non-effectiveness (or even pro-metastatic effect) against various cancer types, see Applicant’s remarks, pg. 7 of 10, paragraph 2.
With respect to Applicant’s arguments (I)-(J), the Examiner notes Prudent teaches the EDCs of Example 8, specifically EDC2.2, as useful in treating many types of cancers such as large and non-small cell lung, colon, pancreatic, breast, head and neck, small cell lung, melanomas and myelomas as demonstrated in Table 1 as discussed above, and thus said demonstration provides support that Prudent’s EDCs are effective and have general anti-cancer activity.
(K) Its entirely unclear how the teachings of Brunicardi would be combined with the teachings of Prudent, as Brunicardi is related to treatment with digoxin in a combination therapy, while Prudent relates to treatment with an EDC comprising any Na+/K+ inhibitor only, see Applicant’s remarks, pg. 8 of 10, last paragraph.
(L) Brunicardi actually states the composition comprises 0.125 mg to 0.25 mg digoxin and not that the daily dose of digoxin is 0.125 mg to 0.25 mg, as required in pending claim 6, see Applicant’s remarks, pg. 9 of 10, paragraph 1.
(M) It is not at all apparent to the skilled person whether the same level of digoxin is required for treatment using an EDC of Prudent comprising digoxin as the Na+/K+ ATPase inhibitor, see Applicant’s remarks, pg. 9 of 10, paragraph 2.
With respect to Applicant’s arguments (K)-(M), the Examiner notes Prudent teaches the pharmaceutically effective amount of EDC administered per dose will be in the range of about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient body weight per day, see paragraph [0270].
The Examiner also notes the range of 0.1 to 20 mg/kg per day encompasses the claimed range of claim 6 and overlaps with the range of digoxin as taught by Brunicardi.
The Examiner further notes Brunicardi teaches compositions of matter than comprise metaformin, a statin, and a cardiac glycoside where the composition is in the form of a pill or tablet and comprises a daily dose of these agents that is within the ranges approved for use of those agents in humans by the Food and Drug administration, see pg. 15, lines 11-13 and 23-27.
Finally, Brunicardi exemplifies the level of digoxin for treatment is typically 0.5-2 ng/mL, and since this is a narrow therapeutic index, it is therefore important the digoxin concentration be maintained in approximately this range if it is used in patients with other conditions such as heart failure.
Thus, it would have been within the scope of the artisan in view of the teachings of Prudent and Brunicardi to provide a daily dose of digoxin as required in pending claim 6 and at a serum range as required in pending claim 7, because the Examiner notes said ranges of administering digoxin overlap as taught by Prudent and Brunicardi.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5, 10 and 17 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Prudent (Published 10 July 2014, US-20140193436-A1, PTO-892 mailed 10/29/2025) as evidenced by Aceto et al. (hereafter referred to as "Aceto-2", Published 30 April 2015, WO-2015061091-A1, IDS filed 06/18/2021).
Regarding claim 1, Prudent teaches an extracellular-targeted drug conjugate (EDC) in which a targeting moiety targets a protein associated with an Na+/K+-ATPase, where the EDC is linked to a drug that interacts with the Na+/K+-ATPase through a stable linker useful in the treatment of disease, see abstract.
Prudent teaches the extracellular-targeted drug conjugate (EDC) comprising a targeting moiety linked by a non-cleavable linker to a therapeutic agent, wherein the targeting moiety binds to an extracellular target that is not an Na+/K+-ATPase, and wherein the therapeutic agent acts on the Na+/K+-ATPase, see paragraph [0008].
Prudent teaches binding of the agent to the protein modulates (inhibits or activates) the interaction of the protein with the Na+/K+-ATPase, wherein the agent targets the alpha subunit of the Na+/K+-ATPase; and the agent is an aglycon of a cardiac glycoside (e.g. required in claim 2), see paragraph [0011].
Prudent teaches various cardiac glycoside agents such as digitoxin (e.g. the cardenolide, required in claims 3-5), digoxin (e.g. the cardenolide, required in claims 3-5) or proscillaridin (e.g. the bufadienolide, required in claims 3-4) and their aglycons are useful in various embodiments of the invention, see paragraph [0217].
Prudent teaches cardiac glycosides bind to the Na+/K+-ATPase and inhibit its pumping activity (e.g. the Na+/K+-ATPase inhibitor, required in claim 1, line 3), see paragraph [0217].
Prudent teaches treating a disease or other medical condition by administering to a patient in need of treatment a therapeutically effective dose of an EDC, see paragraph [0017].
Prudent teaches the treatment of cancer, see paragraph [0018].
Prudent defines “cancer” to include any number of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other parts of the body (e.g., metastasize) (e.g. metastasis in cancer, required in claim 1, line 1); as well as any of a number of structural characteristics and/or molecular features, see paragraph [0038].
Prudent teaches these EDC are generally useful in the treatment of cancer, exemplifying diseases for cancer treatment include breast cancer (e.g. the cancer, required in claim 10 and claim 17), prostate cancer (e.g. the cancer, required in claim 10) and pancreatic cancer, see paragraph [0243].
Prudent defines “treating” and “treatment” of cancer or metastatic cancer refers to the treatment, amelioration or prevention of cancer, including abatement, remission; diminishing the symptoms or making the disease more tolerable; slowing the rate of degeneration or decline; or making the final point of degeneration less debilitating, see paragraph [0074].
With respect to the limitation “wherein the cancer is characterized by the presence of CTC clusters in the bloodstream”, required in claim 1, line 2; the Examiner reasonably interprets this limitation to be a physical limitation of the metastasized cancer recited in claim 1, line 1, and since Prudent defines cancer to include a disease characterized by uncontrolled abnormal proliferation of cells through the bloodstream and lymphatic system to other parts of the body (e.g., metastasize) which itself includes any number of structural characteristics and/or molecular features; and exemplifies treating breast cancers specifically with an EDC of Prudent; the Examiner reasonably interprets the physical limitation is met by the cancer recited by Prudent as discussed above.
Additionally, the Examiner reasonably interprets the breast cancer of Prudent includes the presence of CTC clusters in the bloodstream as required in claim 1, line 2; as evidenced by Aceto-2 who observed the identification of clusters of CTCs (CTC-clusters) in the circulation (e.g. bloodstream) of patients with cancer as demonstrated herein using a combination of breast cancer patient samples, mouse models and next-generation sequencing; that breast CTC-clusters highly represent the metastatic precursor population within breast CTCs; and that disruption of CTC-clusters is associated with diminished metastatic spread, see paragraph [00165].
Moreover, with respect to the limitation of “the disruption of circulating tumor cell (CTC) clusters”, required in claim 1, line 5; the Examiner reasonably interprets this limitation to be a functional consequence of administering the Na+/K+ ATPase inhibitor, recited in claim 1, line 3. Since Prudent teaches the treatment of cancer, specifically breast cancer, by administering a therapeutically effective dose of an EDC that is stably linked to a therapeutic agent, specifically a cardiac glycoside, exemplified as digoxin as discussed above in treating cancer, including metastasized cancer as defined by Prudent above, the functional consequence as recited above will be met by the method of Prudent as discussed above.
Thus, the teachings of Prudent anticipate claims 1-5, 10 and 17.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 6-7 remain rejected under 35 U.S.C. 103 as being unpatentable over Prudent (Published 10 July 2014, US-20140193436-A1, PTO-892 mailed 10/29/2025) as evidenced by Aceto-2 (Published 30 April 2015, WO-2015061091-A1, IDS filed 06/18/2021) as applied to claims 1-5, 10 and 17 above, and further in view of Brunicardi et al. (Published 08 March 2018, WO-2018044369-A2, PTO-892 mailed 10/29/2025).
Prudent as evidenced by Aceto-2 address claims 1-5, 10 and 17 as written above.
Prudent further teaches for treatment of disease the appropriate dosage of an EDC will depend on the type of disease to be treated, the severity and course of the disease, previous therapy, the patient's clinical history and the discretion of the attending physician, see paragraph [0278].
Prudent further teaches exemplary unit dosage formulations contain a daily dose of the active ingredient, see paragraph [0273].
Although, Prudent does not teach wherein (a) the daily dose of digoxin is 0.125 mg to 0.25 mg, required in claim 6; and (b) a digoxin serum level is adjusted to between 0.70 ng/ml and 1.0 ng/ml, required in claim 7.
However, in the same field of endeavor of administering digoxin in treating cancer, Brunicardi teaches a triple drug combination comprising metformin, simvastatin and digoxin for targeted treatment of pancreatic cancer, see title.
Brunicardi exemplifies within the combination administered to the patient contains 0.125-0.250 milligrams of digoxin (e.g. the amount of digoxin, required in claim 6, line 2), see pg. 3, lines 20-25.
Brunicardi exemplifies the level of digoxin for treatment is typically 0.5-2 ng/mL, and since this is a narrow therapeutic index, it is therefore important the digoxin concentration be maintained in approximately this range if it is used in patients with other conditions such as heart failure (e.g. the digoxin serum level, required in claim 7, lines 2-3), see pg. 18, lines 14-17.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have included limitations (a)-(b) as taught by Brunicardi above into the method of treating cancer in the patient as taught by Prudent above as within the scope of the artisan as combining prior art elements according to known methods to yield predictable results.
One of ordinary skill in the art would have been motivated to include both limitations (a)-(b) into the method of Prudent as discussed above in order to administer the appropriate dosage of the EDC of Prudent in treating the patient of Prudent; particularly wherein the patient as taught by Brunicardi has other conditions such as heart failure as taught by Brunicardi above. One of ordinary skill in the art would have had a reasonable expectation of success of including limitations (a)-(b) into the method of Prudent as discussed above; as Prudent and Brunicardi are both drawn to administering digoxin in treating cancer; and Prudent teaches the appropriate dosage of the EDC will depend on and include the patient's clinical history.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
Conclusion
No claims are allowed in this action.
THIS ACTION IS MADE FINAL. 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 JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
Prosecution Insights