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 .
Priority
Acknowledgment is made of applicant’s claim for priority based on a provisional application filed as 63/227,209 on 07/29/2021.
All claims are given the priority date of 07/29/2021.
Application Status
Receipt is acknowledged of amendment, filed 01/29/2024. Claims 1-8 and 10-20 are currently pending.
Information Disclosure Statement
Receipt of acknowledgment of the information disclosure statement filed on 01/29/2024 have been received and all references have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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 paragraph [0071]. See MPEP § 608.01.
Claim Objections
Claim 5 is objected to because of the following informalities:
Claim 5 recites “The method of claim, 1”. The claim should be amended to recite “The method of claim 1,”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1, 4-6, 8, 10 and 11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 11 are drawn to a genus of LCN2 inhibitors. The rejected claims thus comprise a genus of LCN2 inhibitors that encompass any inhibitors, such as small molecules, capable of inhibiting overexpression of LCN2.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes a structure-based virtual screening approach identified potential chemical inhibitors of LCN2 [0007]. The specification describes Four out of sixteen selected compounds significantly decreased cell proliferation, cell viability and the AKT phosphorylation levels in SUM149 cells and moreover, ectopically expressing LCN2 MCF7 cells, treated with two LCN2 inhibitors (ZINC00784494 and ZINC00640089) showed a significant decrease in cell proliferation, and the two compounds (ZINC00784494 and ZINC00640089) reduced cell viability and colony formation of IBC cells [0007; 0051]. The specification describes that compounds ZINC00784494, ZINC00640089, ZINC00230S67, and ZINC00829S34 significantly reduced the number of colonies formed at 10 μM (42%, 62%, and 41 % reduction, respectively) compared to DMSO [0052]. No description is provided of a representative number of small molecules or a structure-function correlation to allow one to envision a representative number of small molecules that would be capable of inhibiting the overexpression of LCN2.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of the four successful small molecules, such as ZINC00230567, ZINC00829534, ZINC00784494 and ZINC00640089 [0051]. The results are not necessarily predictive of any small molecule that would be capable of inhibiting overexpression of LCN2. Thus, it is impossible for one to extrapolate from the few examples described herein those small molecule inhibitors that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of any small molecules capable of inhibiting LCN2 overexpression.
Zheng et al (Mar. Drugs 2025, 23(1), 24; Pgs. 1-21) teaches that while several LCN2-related chemicals have been identified, the lengthy drug development process and complex procedures for chemical extraction and synthesis have made it challenging to find inhibitor molecules with clear clinical benefits (Page 2, Paragraph 1).
Santiago-Sanchez et al (Int. J. Mol. Sci. 2021, 22(16), 8581; pgs 1-19) teaches in silico analysis with a library of 25,000 compounds to identify potential LCN2 inhibitors, and four out of sixteen selected compounds significantly decreased cell proliferation, cell viability, and the AKT phosphorylation levels in SUM149 cells (Page 1, Abstract). Santiago-Sanchez teaches that ectopically expressing LCN2 MCF7 cells, treated with two potential LCN2 inhibitors (ZINC00784494 and ZINC00640089) showed a significant decrease in cell proliferation (Page 1, Abstract). Santiago-Sanchez teaches compounds ZINC00784494, ZINC00640089, ZINC00230567, and ZINC00829534 significantly reduced the number of colonies formed at 10 µM (42%, 62%, and 41% reduction, respectively) compared to DMSO and any of the four compounds significantly reduced the number of colonies at concentrations of 1 µM or 0.1 µM (Page 8, Paragraph 3). Santiago-Sanchez teaches that screening for LCN2 (Lipocalin-2) small-molecule inhibitors relies on a combined approach of in silico (computational) docking and in vitro (cell-based) viability or binding validation (Page 2, Paragraph 3).
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 4-6, 8, 10 and 11.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2, 3, 7 and 8 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. A dependent claim (e.g. Claim 3) can only rely on a claim with a lower number (e.g., Claim 1 or Claim 2). Claim 2 currently relies on claim 11. Claim 3 currently relies on claim 12. Claim 7 currently relies on claim 12. Claim 8 currently relies on claim 11. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 3, 4, 6, 7, 10 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Naito et al (US 2008/0113351 A1) in view of Villodre et al (bioRxiv, March 18th, 2021; 1-29).
Regarding claims 1, 3, 4, 10 and 12, Naito teaches using siRNAs for targeting LCN2 for the treatment of breast cancer (Page 6, Fig. 6; [0159, 0256 and 0268]). Naito teaches the sequence of SEQ ID NO: 273714 which is 100% identical to the entire sequence of instant SEQ ID NO: 2 (See Appendix I).
Naito does not teach the treatment of breast cancer, which is inflammatory breast cancer (IBC) and does not teach reducing metastasis.
Villodre teaches depletion of LCN2 resulted in inhibited tumor growth, skin invasion, and brain metastasis in mouse models of inflammatory breast cancer (IBC) (Page 2, Lines 9-12). Villodre teaches a method of inhibiting overexpression of lipocalin-2 by administering shRNAs to SUM149 inflammatory breast cancer cells (referred to as KCN2 knockdown cells) wherein the cells were then administered to the mice via injected into the mammary fat pad (Page 4, lines 64-67 and Page 8, Lines 153-170). Villodre teaches that the administration of the shRNAs to SUM149 IBC cells showed reduced expression of LCN2 compared to the control lines as well as reduced proliferation and viability (Page 24, Fig 2A and 2D). Villodre teaches the functional role of LCN2 in IBC brain metastasis by using the HER2+ MDA-IBC3 mouse model, which has a high propensity to metastasize to the brain and has been used to identify targets and develop therapeutics against brain metastasis and it was found that the brain metastatic burden was significantly lower in mice that had received tail-vein injection of LCN2-silenced MDA-IBC3 cells than in mice injected with control cells (Page 12, Lines 256-261).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the treatment of general breast cancer as taught by Naito for the specific treatment of inflammatory breast cancer using targeted inhibitors of LCN-2 as taught by Villodre because Naito teaches it is within the ordinary skill in the art to use siRNAs for targeting LCN2 for the treatment of breast cancer and Villodre teaches the brain metastatic burden was significantly lower in mice that had received tail-vein injection of LCN2-silenced MDA-IBC3 cells than in mice injected with control cells.
One would have been motivated to make such a modification in order to receive the expected benefit of the depletion of LCN2 resulted in inhibited tumor growth, skin invasion, and brain metastasis in mouse models of inflammatory breast cancer (IBC) as taught by Villodre.
Regarding claims 6 and 7, Villodre teaches that the administration of the shRNAs to SUM149 IBC cells showed reduced expression of LCN2 compared to the control lines as well as reduced proliferation and viability (Page 24, Fig 2A and 2D) wherein SUM149 cells do not express HER2 or EGFR are expressed (Page 10, Line 218).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the treatment of general breast cancer as taught by Naito for the specific treatment of inflammatory breast cancer using targeted inhibitors of LCN-2 as taught by Villodre because Naito teaches it is within the ordinary skill in the art to use siRNAs for targeting LCN2 for the treatment of breast cancer and Villodre teaches the administration of the shRNAs to SUM149 IBC cells showed reduced expression of LCN2 compared to the control lines as well as reduced proliferation and viability.
One would have been motivated to make such a modification in order to receive the expected benefit of the depletion of LCN2 resulted in inhibited tumor growth, skin invasion, and brain metastasis in mouse models of inflammatory breast cancer (IBC) as taught by Villodre.
Claims 5, 8 and 11 are rejected under 35 U.S.C. 103 as being unpatentable by Naito et al (US 2008/0113351 A1) in view of Villodre et al (bioRxiv, March 18th, 2021; 1-29), as applied to claims 1, 3, 4, 6, 7, 10 and 12 above, and further in view of Chappell et al (Cell Cycle. 2012 Dec 1;11(23):4447-61).
The teachings of Naito and Villodre as described and applied above.
Regarding claims 5, 8 and 11, Naito and Villodre do not teach wherein the LCN2 inhibitor is a small molecule.
Chappell teaches co-delivery as well as single delivery of the small molecule LCN2 inhibitor KN-93 to MCF-7/NGAL cells (Page 4452, Column 1 bridging Column 2). Chappell teaches MCF-7/NGAL cells were highly sensitive to the constant dose of KN-93 in the presence of different concentrations of doxorubicin, as well as, the dose of250 nM KN-93 synergized with doxorubicin and lowered the doxorubicin IC50 in both MCF-7/pLXSN and the doxorubicin- resistant MCF-7/DoxR cells (Page 4453, Column 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the siRNA inhibitor of Naito for the use of the small molecule KN-93 LCN2 inhibitor as taught by Chappell because Naito teaches it is within the ordinary skill in the art to use siRNAs for targeting LCN2 for the treatment of breast cancer, Villodre teaches the brain metastatic burden was significantly lower in mice that had received tail-vein injection of LCN2-silenced MDA-IBC3 cells than in mice injected with control cells and Chappell teaches using traditional chemotherapy in combination with the KN-93 LCN2 inhibitor in order to reduce chemotherapy sensitivity and decrease expression of LCN2.
One would have been motivated to make such a modification in order to receive the expected benefit of more effective treatment of cancer using both traditional chemotherapy and the small molecule KN-93 LCN2 inhibitor in combination as taught by Chappell.
Allowable Subject Matter
Claims 13-20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant is advised that should claims 13-16, respectively, are be found allowable, claims 17-20, respectively, will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm 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, JENNIFER A DUNSTON can be reached at (571) 272-2916. 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.
/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights