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 .
Application Status and Election
Applicant’s amendments and election without traverse of the species of S100A8/9 inhibition in the reply filed on August 6, 2025 are acknowledged. Claims 1-6, 8-12, 14-18, 20 and 30-32 are pending.
Claims 8-12 and 14-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.
Claims 1-6, 17-18, 20 and 30-32 are under examination.
Drawings
The drawings are objected to because the text in many of the figures is not sufficient to provide satisfactory reproduction characteristics. 37 CFR 1.84(l) states that “all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.” In the instant case, the text in FIGs 1A, 1G, 2A-C, 2F, 3D, 4B, 4E, 5C-D, 5F, 6E-F, 7A-B, 7D-E, 8A-D, 9A-C, 9F, 10A-B, 10D, 11A-D, 12A-C, 12E, 13D-E, 14B, 15B-F, 16D is light grey, too small, or too low resolution or otherwise not sufficiently dense and dark to permit satisfactory reproduction characteristics.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 13. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is also objected to because the use of the terms Astrios®, CellTrace®, DuoSet®, Nupage®, TWEEN®, Sytox®, Quant-Seq®, TapeStation®, NextSeq®, and GraphPad®, which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 6 and 18 are objected to because of the following informalities:
Claim 6 recites “an anti-A100A8/9 antibody”, which is a typographical error. An inhibitor of S100A8/9 would be “an anti-S100A8/9 antibody”.
Claim 18 recites “The method according to claim 17, wherein… (c) wherein the cancer is…”, which is grammatically incorrect due to the double recitation of “wherein”.
Appropriate correction is required.
Claim Interpretation
Claims 1 and 17 recite “reactivation of dormant tumor cells”. The Specification does not define cell dormancy or cell reactivation. However, the Specification does describe cell dormancy as encompassing at least two states: quiescence and senescence (page 1). The Specification describes quiescence as “the reversible state of cell arrest in which cells regain the ability to re-enter the cell cycle”, while senescence is a stress response that pauses the cell cycle, but that is also reversible in cancer cells (page 1). Based on this description “a dormant tumor cell” is interpreted as a cell that is not actively replicating/proliferating and paused somewhere in the cell cycle.
A review by Giancotti teaches that when tumor cells metastasize from their primary site, there is a period of cell dormancy between extravasation and outgrowth of the initial cell colonization (Giancotti, Cell (2013), 155: 750-764; Figure 1). Giancotti teaches that this “metastatic dormancy” is due to cancer cells adopting/evolving strategies to survive and proliferate in the new tissue/organ (page 750, ¶2-3). Giancotti teaches that the metastasized tumor cells must establish a premetastatic niche through angiogenic and other tissue remodeling signaling pathways before it is capable of proliferating and establishing a secondary cancer site (page 757, ¶3-4). Giancotti teaches that pre-metastatic cells undergo an epithelial-to-mesenchymal transformation (EMT) during the invasion and/or intravasation stages of metastasis (Figure 1, legend), which then must be reversed via a mesenchymal-to-epithelial transformation (MET) upon reaching the secondary site, which may be responsible for the perceived cancer cell dormancy (page 758, ¶2-4).
Based on the Specification and Giancotti’s review article “reactivation of a dormant tumor cell” 1) is interpreted as causing a primary tumor or metastatic cancer cell that has a paused cell cycle to start and/or complete the cell cycle resulting in cell replication/proliferation, and 2) encompasses cells that have metastasized to a location that is different from the primary tumor site and establishes a secondary tumor and/or undergoes an MET after a delayed period of time.
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.
Claim 18 is 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.
Claim 18 recites “The method according to claim 17, wherein” followed by clauses (a), (b) and (c). However, there are no conjunctions between (a), (b) and (c). It is unclear whether all three limitations in (a), (b) and (c) are required or only a single limitation is required.
If all three are required, it is suggested that “and” is included between clauses (b) and (c).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 6, 17, 20 and 30-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Filvaroff (US 20100055099 A1, published March 4, 2010). Claims 30-32 are evidenced by Srikrishna (Geetha Srikrishna. J Innate Immun (2012), 4: 31-40).
Regarding claims 1-2, Filvaroff teaches that a tumor begins as a single aberrant cell which can proliferate only to a size of a few cubic millimeters due to distance form available capillary beds, where it can stay dormant without further growth and dissemination for a long period of time ([0006]). Filvaroff teaches VEGF-negative mammary glands had increased tumor latency (i.e., tumor cells were dormant) ([0349]). Filvaroff teaches VEGF-negative tumors have increased mRNA levels of S100A8 and S100A9 ([0375]). Filvaroff teaches that tumor cells deprived of VEGF become more responsive to other factors for survival, growth and migration ([0385]). Filvaroff teaches treating subjects having a VEGF-independent tumor (i.e., a dormant tumor cell) with S100A8 and S100A9 antagonists (i.e., inhibitors) ([0019]).
Regarding claim 6, the specification states that an anti-S100A8/A9 antibody includes “an antibody that binds to, blocks, competes or interferes with binding or activity of, any of the components of S100A8/ A9, or the heterocomplex itself.” (page 20, lines 16-18). Therefore, a neutralizing antibody that blocks either S100A8 or S100A9 is encompassed by “an anti-S100A8/9 antibody”.
Filvaroff teaches that an S100A8 antagonist of the invention is an anti-S100A8 antibody ([0129]). Filvaroff teaches that an S100A9 antagonist of the invention is an anti-S100A9 antibody ([0130]).
Regarding claim 17, Filvaroff teaches VEGF-negative tumors have increased mRNA levels of S100A8 and S100A9 compared to VEGF+ tumors (i.e., a control sample) ([0375]). Filvaroff teaches treating subjects having a VEGF-independent tumor (i.e., a dormant tumor cell with increased S100A8 and S100A9 levels) with S100A8 and S100A9 antagonists (i.e., inhibitors) ([0019]).
Regarding claim 20, Filvaroff teaches administering S100A8 and S100A9 antagonists with one or more chemotherapeutic agents ([0234], [0336]).
Regarding claims 30-32, as indicated above for claims 1-2, Filvaroff teaches treating a subject having a VEGF-negative resistant cancer (i.e., dormant cancer cells) with S100A8 and S100A9 antagonists. Filvaroff teaches using antagonists S100A8 and S100A9 for treatment of relapsed tumor growth (i.e., recurrence of cancer) ([0232]-[[0234]).
Filvaroff is silent on whether S100A8/A9 is in the stress-induced b-adrenergic signaling pathway.
Srikrishna teaches that expression of S100A8 and S100A9 is enhanced by the stress response modulator norepinephrine (i.e., b-adrenergic pathway agonist) (page 32, ¶3). Therefore, S100A8 and S100A9 are components in the stress-induced b-adrenergic signaling pathway, and Filvaroff’s teaching of using S100A8 and S100A9 antagonists to prevent relapse cancer cell growth inherently comprises inhibiting stress-induced b-adrenergic pathway signaling.
Claims 1-2, 17-18, 20, and 30-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee (EunMi Lee. Thesis: Immune Regulation of Tumor Cell Plasticity: A Promising Molecular Target in Breast Cancer Metastasis, Augusta University, October 2018). Claims 30-32 are evidenced by Srikrishna (Geetha Srikrishna. J Innate Immun (2012), 4: 31-40).
Regarding claims 1-2, Lee teaches a mouse model in which tumor cells are disseminated (page 64). Lee teaches that disseminated tumor cells are present in lymph nodes and lungs for up to 12 weeks without developing metastatic tumors (page 64), which is interpreted as encompassing “dormant tumor cells”. Lee teaches that lung-derived granulocyte myeloid-derived suppressor cells (gMDSCs) enhance metastatic growth (i.e., reactivate) of the disseminated tumor cells (page 64; Figure 22). Lee teaches that S100A8/9 induce MDCSs in vitro (Fig 25) and induces non-proliferative tumor cells to adopt the proliferative MET phenotypes in vivo (page 27, Fig 27A-B, 28A-B). Lee teaches compound #10 is a calprotectin (i.e., S100A8/9 complex) inhibitor (Figure 33A). Lee teaches compound #10 suppressed calprotectin-induced cell proliferation in vitro (Figure 34 A-B). Lee teaches administering compound #10 to mice (i.e., a subject) which results in suppression of metastasized tumor growth by disseminated tumor cells (i.e., inhibited reactivation of dormant cells) (pages 86-88; Fig 35).
Regarding claim 17, as indicated above for claims 1-2, Lee teaches treating mice with Compound #10, which is a S100A8/A9 inhibitor. Lee teaches measuring levels of S100A8 and S100A9 in primary and metastatic breast cancer patient (page 66). Lee teaches S100A8/A9 are significantly higher in metastatic breast tissue (i.e., increased levels of S100A8/9 indicate the presence of reactivated dormant tumor cells in a subject) (Figs 23, 31).
Regarding claim 18, the claim is indefinite for the reasons described above in paragraph 19. For the purposes of examination, claim 18 is interpreted as only on one (a), (b) or (c) is required. Lee teaches detecting higher levels of A100A8 and S100A9 in blood samples (page 79; Fig 31).
Regarding claim 20, Lee teaches treating the mice with both compound #10 and cyclophosphamide, a chemotherapeutic agent (page 86, Fig 35).
Regarding claims 30-32, as indicated above for claims 1-2, Lee teaches treating mice with Compound #10, which is a S100A8/A9 inhibitor and which reduces S100A8/A9-induced metastasis (i.e., recurrence of cancer).
Lee is silent on whether S100A8/A9 is in the stress-induced b-adrenergic signaling pathway.
Srikrishna teaches that expression of S100A8 and S100A9 is enhanced by the stress response modulator norepinephrine (i.e., b-adrenergic pathway agonist) (page 32, ¶3). Therefore, S100A8 and S100A9 are components in the stress-induced b-adrenergic signaling pathway, and Lee’s method of treating mice with Compound #10 inherently comprised inhibiting stress-induced b-adrenergic pathway signaling.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Lee (EunMi Lee. Thesis: Immune Regulation of Tumor Cell Plasticity: A Promising Molecular Target in Breast Cancer Metastasis, Augusta University, October 2018) as applied to claims 1-2, 17-18, 20, and 30-32 above, and further in view of Olsson (Olsson et al., Journal for ImmunoTherapy of Cancer (2015) 3:53, 1-14).
The teachings of Lee are recited above as for claims 1-2, 17-18, 20 and 30-32.
Lee does not teach treating a subject with tasquinimod.
Olsson teaches tasquinimod is a small molecule immunotherapy with demonstrated effects on the tumor microenvironment (TME) involving immunomodulation, anti-angiogenesis and inhibition of metastasis (Abstract, background). Olsson teaches tasquinimod targets S100A9 (Abstract, background). Olsson teaches administering tasquinimod to the 4T1 breast cancer mice model (i.e., a subject) reduced tumor growth and the number of lung metastatic nodes (i.e., reduced reactivation of dormant tumor cells) (Abstract; Fig S1). Olsson teaches that tasquinimod is already in phase II and phase III clinical trials for prostate cancer (page 2, ¶3).
It would have been obvious to one skilled in the art to have used tasquinimod in the method of Lee for reducing MDCS-mediated dormant metastatic cell proliferation. It would have amounted to the simple substitution of one S100A8/A9 inhibitor for another by known means to yield predictable results. The skilled artisan would have predicted that tasquinimod would inhibit MDCS-mediated metastatic cell proliferation because Lee teaches that tasquinimod is effective for decreasing lung metastasis in the 4T1 breast cancer model, which is the same model that Lee demonstrates the role of S100A8/A9 on activation of MDCS-mediated metastatic cell proliferation. The skilled artisan would have been motivated to make the substitution because tasquinimod has already been through several phase II and phase III clinical trials indicating that tasquinimod is safe for cancer treatment in humans.
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Lee (EunMi Lee. Thesis: Immune Regulation of Tumor Cell Plasticity: A Promising Molecular Target in Breast Cancer Metastasis, Augusta University, October 2018) as applied to claims 1-2, 17-18, 20, and 30-32 above, and further in view of Vrakas (Vrakas et al., Immunological Investigations (2015), 44: 174-188, Early Online version point citations) and Barrueco (Rodriguez-Barrueco et al., Genes and Development (2015), 29: 1631-1648).
The teachings of Lee are recited above as for claims 1-2, 17-18, 20 and 30-32.
Lee does not teach lowering the levels of A100A8 or S100A9 using siRNA.
Vrakas teaches S100A8 expression and levels of MSDCs increases in the lungs (i.e., the premetastatic niche) as a primary tumor in the 41T mouse mode processes (page 7; Figs 2-3). Vrakas suggests reducing S100A8 levels in tumor cells by expressing S100A8 shRNAs (i.e., using siRNA) (page 13, ¶4).
Barrueco teaches HER2-positive breast cancers secrete high levels of IL-6, which promotes increases in the calprotectin S100A8/A9 complex production and secretion (Abstract). Barrueco teaches increasing calprotectin activates cell proliferation signaling pathways (Abstract). Barrueco teaches expressing shRNAs targeted to S100A8 and S100A9 in MCF-10A/Erb2* cells (i.e., breast cancer cell lines) (page 1639, ¶4). Barrueco teaches expressing S100A8 and S100A9 shRNAs in the breast cancer cell lines inhibited their proliferation and tumor growth in vivo (page 1639, ¶4; Fig 5C-E).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have reduced the expression of S100A8 and/or S100A9 using the siRNA-generating shRNA vectors of Barrueco in Lee’s method for reducing MDCS-mediated dormant metastatic cell proliferation. It would have amounted to the simple substitution of one means for inhibiting S100A8/A9 for another by known means to yield predictable results. The skilled artisan would have predicted that S100A8/A9 mRNA inhibiting methods would inhibit MDCS-mediated metastatic cell proliferation because Barrueco teaches that expressing S100A8/A9 shRNA is effective of decreasing tumor growth of breast cancer cells in vivo. The skilled artisan would have been motivated to make the substitution because Vrakas suggests inhibiting S100A8/A9 using shRNA in the 41T mouse model of breast cancer to lung metastasis.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Lee (EunMi Lee. Thesis: Immune Regulation of Tumor Cell Plasticity: A Promising Molecular Target in Breast Cancer Metastasis, Augusta University, October 2018) as applied to claims 1-2, 17-18, 20, and 30-32 above, and further in view of Fang (Fang et al., Oncotarget (2015), 6: 28401-27424; cited #19 on IDS filed 4/19/2023).
The Specification states that an anti-S100A8/A9 antibody includes “an antibody that binds to, blocks, competes or interferes with binding or activity of, any of the components of S100A8/ A9, or the heterocomplex itself.” (page 20, lines 16-18). Therefore, a neutralizing antibody that blocks either S100A8 or S100A9 is encompassed by “an anti-S100A8/9 antibody”.
The teachings of Lee are recited above as for claims 1-2, 17-18, 20 and 30-32. Lee also teaches that S100A8 and S100A9 act in a paracrine fashion to activate signaling pathways to promoter tumor cell growth (page 72).
Lee does not teach treating a subject with an anti-S100A8/9 antibody.
Fang teaches S100A9 levels are elevated in early-stage oral cancer patients (Abstract). Fang teaches S100A9 is secreted into the extracellular space and enhances tumor cell invasion, monocyte migration and angiogenic activity (Abstract). Fang teaches patients with high S100A9 expression in the stroma had shortest recurrence-free survival (Abstract). Fang teaches administering neutralizing anti-S100A9 antibodies to cell culture attenuated the S100A9-mediated, paracrine-signaling for cell proliferation, migration, invasion and monocyte recruitment (page 28417 ¶1; Fig 4E-F).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have administered the neutralizing anti-S100A9 antibody of Fang in Lee’s method for reducing MDCS-mediated dormant metastatic cell proliferation. It would have amounted to the simple substitution of one means for inhibiting S100A8/A9 for another by known means to yield predictable results. The skilled artisan would have predicted that the anti-S100A9 antibody would inhibit MDCS-mediated metastatic cell proliferation because Fang teaches the anti-S100A9 antibody is effective at reducing S100A8/A9 paracrine signaling that induces cell proliferation and Lee also teaches that S100A8/A9 functions by paracrine signaling to increase tumor cell proliferation. The skilled artisan would have been motivated to make the substitution because Fang demonstrates the anti-S100A9 antibody is effective at reducing proliferation of cancer cells.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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, Ram Shukla can be reached at (571)272-0735. 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.
/CATHERINE KONOPKA/Examiner, Art Unit 1635