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 .
DETAILED ACTION
Status of Application/Election/Restrictions
Applicant’s election of Group I (claims 1-8 and 12-13), neutralizing antibody/antibody to the receptor and melanoma/cutaneous malignant melanoma/melanoma tumorigenesis/skin cancer in the reply filed on November 18, 2025 is 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)).
Claim 10 is canceled. Claims 1-9 and 11-13 are pending in this application. Claims 9 and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Claims 6 and 12 are also withdrawn from further consideration because of non-elected species. Upon reconsideration, the species election on different cancer is withdrawn because the subject matter can be found in the same prior art reference. The subject matter to the extent of different cancers recited in claim 8 is included and under examination in this office action. Election was treated as without traverse in the reply filed on November 18, 2025.
Claims 1-5, 7-8 and 13 are under examination with respect to neutralizing antibody or antibody to the receptor in this office action.
Claim Rejections - 35 USC § 112
5. 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 1-5, 7-8 and 13 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 pre-AIA the applicant regards as the invention.
Claims 1-5, 7-8 and 13 are indefinite because:
i. Claim 1 recites the limitation "the step" in lines 1-2 of the claim. There is insufficient antecedent basis for this limitation in the claim.
ii. Claim 7 recites the limitation "the receptor" in line 3 of the claim. There is insufficient antecedent basis for this limitation in the claim.
iii. The rest of claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
6. 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 1-5, 7-8 and 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for detecting increased systemic LCN2 levels in blood or CSF isolated from a patient with brain metastases compared to healthy control or neutralizing or reducing LCN2 levels induced by a melanoma conditioned medium in primary astrocytes cultured in a culture medium comprising a melanoma conditioned medium and a structurally and functionally defined anti-LCN2 neutralizing antibody compared to primary astrocytes cultured in in a culture medium comprising a melanoma conditioned medium without the LCN2 neutralizing antibody, or neutralizing or reducing systemic LCN2 levels in blood or circulating astrocytes in a patient with brain metastases compared to a healthy control by administering to the patient in need thereof a composition comprising a structurally and functionally defined anti-LCN2 neutralizing antibody, does not reasonably provide enablement for a method for treating or preventing brain metastases using structurally and functionally undefined LCN2 inhibitor or neutralizing antibody or agent that interferes in systemic LCN2 signaling pathways or reduces LCN2 expression or any combinations thereof as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. In addition, the specification does not enable the invention of claims 1-5, 7-8 and 13 that is directed to a method of prevention.
“There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is ‘undue’. These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)”. See MPEP § 2164.01.
Claims 1-5, 7-8 and 13 are drawn to a method for treating or preventing brain metastases comprising the step of administering to a patient in need a composition comprising a therapeutically effective amount of LCN2 Inhibitor, an agent that interferes in systemic LCN2 signaling pathways, an agent that reduces LCN2 expression, or any combination thereof including LCN2 neutralizing antibody/antibody to the receptor.
The claims encompass methods for treating or preventing brain metastases using a structurally and functionally undefined LCN2 Inhibitor, an agent that interferes in systemic LCN2 signaling pathways, an agent that reduces LCN2 expression, or any combination thereof including a structurally and functionally undefined LCN2 neutralizing antibody/antibody to the receptor.
The instant invention is based on findings that:
i) The LCN2 protein levels in plasma and CSF isolated from melanoma and breast cancer-derived metastases-bearing mice were upregulated compared to healthy mice. The LCN2 protein levels in blood sample isolated from human patients with brain metastasis from melanoma, breast cancer or lung carcinoma were upregulated compared with healthy controls (Example 1, Figures 1A-1L);
ii) The survival of wild type mice with melanoma and breast cancer-derived brain metastases was reduced compared with LCN2-/- mice with melanoma and breast cancer-derived brain metastasis (Example 2, Figures 2A-2F). The lower level of LCN2 correlates with longer survival in patients with melanoma-derived brain metastasis (Example 5, Figures 6C-D);
iii) The expression of LCN2 receptor, SLC22A17 in astrocytes was highest in melanoma and breast-derived brain metastases bearing mice; and was highest in CD45- stromal cells in human patients with brain metastases from melanoma, lung and breast cancer and primary brain tumors compared to healthy controls (Example 3, Figures 3A-3C; Example 5, Figures 6A-C6). The expression of cytokines and chemokines was significantly reduced in astrocytes isolated from brain metastases of LCN2-/- mice compared to WT brain metastases and so is NF-kB P65 subunit (Eaxmple3, Figure 3D-3H). The expression of immunosuppressive gene signature in both melanoma and breast cancer-derived brain metastases in WT mice is upregulated but not in brain metastases of LCN2-/- mice (Figure 4A-D); and
iv) Melanoma conditioned medium (CM) upregulated expression of gliosis-related signature genes in primary astrocytes cultured in the melanoma CM, and this upregulation was attenuated by LCN2 neutralizing antibody or simvastatin (figures 7A-7F).
Applicant extrapolates the above findings to the claimed method for treating or preventing brain metastases comprising the step of administering to a patient in need a composition comprising a therapeutically effective amount of LCN2 Inhibitor, an agent that interferes in systemic LCN2 signaling pathways, an agent that reduces LCN2 expression, or any combination thereof including LCN2 neutralizing antibody or antibody to the receptor.
First, Applicant is not enabled for a method of preventing a person from getting brain metastases. The instant claims recite the limitation “preventing brain metastases by administering to a patient in need a composition comprising a therapeutically effective amount of LCN2 inhibitor…,or any combination thereof”. However, neither the specification nor the prior art provides guidance as to how to prevent a person from having brain metastases. Currently brain metastases cannot be prevented as evidenced by the factsheet of brain metastases (see p. 2 of the factsheet of Brain Metastases retrieved from the Brigham and Women's hospital website). Any individual has potential to develop brain metastases. Applicant fails to teach how to identify or predict when and which person would have brain metastases and predict when the person would need the treatment before the brain metastases occur to prevent the brain metastases from occurring. Neither the specification nor the art teaches that administration of the claimed LCN2 inhibitor or agents or LCN2 neutralizing antibody/antibody to the receptor can prevent a person from getting brain metastases. In addition, the cause of the brain metastases can be due to a genetic mutation, which is a natural process. The specification fails to provide sufficient guidance to enable one of skill in the art to practice the invention without undue experimentation as it pertains to a method of prevention. Further, Applicant also fails to provide specific guidance as to what specific amount of the claimed LCN2 inhibitor or agents or LCN2 neutralizing antibody/antibody to the receptor can be used and thus would be effective to prevent brain metastases. Thus, a skilled artisan cannot contemplate a right amount to prevent the brain metastases or to prevent a person from getting the brain metastases.
Second, based on the specification and the prior art, Applicant is enabled for detecting increased systemic LCN2 levels in blood or CSF isolated from a patient with brain metastases compared to healthy control or neutralizing or reducing LCN2 levels induced by a melanoma conditioned medium in primary astrocytes cultured in a culture medium comprising a melanoma conditioned medium and a structurally and functionally defined anti-LCN2 neutralizing antibody compared to primary astrocytes cultured in the culture medium with no LCN2 neutralizing antibody. Applicant is predicably enabled for neutralizing or reducing systemic LCN2 levels in blood or circulating astrocytes in a patient with brain metastases compared to a healthy control by administering to the patient in need thereof a composition comprising a structurally and functionally defined anti-LCN2 neutralizing antibody. However, detection of an increased expression level of LCN2 in blood sample or astrocytes is not the only cause for brain metastases.
While the skill level in the art is high, the level of predictability is low. Formation of brain metastasis is a complex multistage process that involves diverse signaling pathways and is influenced by the intrinsic molecular subtypes of primary tumors, transcriptional and epigenetic changes accumulated by cancer cells, and the formation of a permissive microenvironment in the brain to seed metastases (see Patel et al. npj Precision Oncology, 2025; 9:31). The use of monoclonal antibody (mAb)-based therapy in the treatment of CNS tumors or brain metastases is still a challenge and restricted by the blood–brain barrier (BBB), which hinders the delivery of the mAb and specific targeting to cell types arising from primary tumors (see Cavaco et al. Pharmaceutics 2020, 12(1), 62; doi.org/10.3390/pharmaceutics12010062).
The specification provides no well-established correlation between reduction of systemic LCN2 levels in blood or circulating astrocytes in a patient with brain metastases compared to a healthy control by administration of a structurally and functionally defined anti-LCN2 neutralizing antibody to the patient and the treatment of brain metastases from different cancers in patients in vivo using the claimed LCN2 Inhibitor or agent including anti-LCN2 neutralizing antibody or antibody to the receptor.
Notably even when a known therapeutic monoclonal antibody which can cause tumor regression of the primary tumor for which the antibody is known to be therapeutically effective is available, it is still unpredictable whether that monoclonal antibody will be able to treat a metastasized secondary tumor of the primary tumor which has metastasized to the brain. For example, Koo et al. teach that the monoclonal antibody trastuzumab, which is effective to treat primary breast tumors expressing the human HER2 antigen in human patients and systemic metastases in these patients, is ineffective to treat metastases which are located in the brain of these patients, most likely because the BBB blocks the monoclonal antibody from being able to target the tumor in the brain (see abstract; Koo et al. Radiat. Oncol. 2016; 34:1-9. Dx.doi.org/10.3857/roj.2016.34.1.1). The specification provides no working example or data from an art accepted animal model to support or demonstrate that administration of the claimed LCN2 Inhibitor or agent including anti-LCN2 neutralizing antibody or antibody to the receptor to the patient with brain metastases from different cancers can treat or prevent brain metastases in vivo. Accordingly, it is highly unpredictable that the claimed LCN2 neutralizing antibody or antibody to the receptor would be able to treat or prevent brain metastases, indicating undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
Further, the specification provides no well-established structural and functional relationship between the claimed LCN2 neutralizing antibody or antibody to the receptor and the anti-LCN2 antibody known in the prior art such as US8481032 or US7645616. The specification fails to teach what other structures/amino acid sequences can or cannot be included/changed in all LCN2 neutralizing antibody or antibody to the receptor in order to preserve the activity of LCN2 neutralizing antibody known in the art in reducing LCN2 levels in blood or circulating astrocytes or even in treating or preventing brain metastases. Thus, a skilled artisan cannot contemplate how to make and use the claimed invention without undue experimentation.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, no working example, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by one of skill in the art to perform in order to practice the claimed invention as it pertains to a method for treating or preventing brain metastases comprising the step of administering to a patient in need a composition comprising a therapeutically effective amount of LCN2 Inhibitor, an agent that interferes in systemic LCN2 signaling pathways, an agent that reduces LCN2 expression, or any combination thereof including LCN2 neutralizing antibody/antibody to the receptor.
Claim Rejections - 35 USC § 112
7. Claims 1-5, 7-8 and 13 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
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 complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claims 1-5, 7-8 and 13 encompass using a genus of LCN2 inhibitor, a genus of agent that interferes in systemic LCN2 signaling pathways, a genus of agent that reduces LCN2 expression or any combination thereof for treating or preventing brain metastases. Claims 7 and 13 encompasses using a genus of neutralizing antibody/antibody to the receptor for treating or preventing brain metastases.
Applicant has not disclosed sufficient species for the broad genus of LCN2 inhibitor, the broad genus of agent that interferes in systemic LCN2 signaling pathways, the broad genus of agent that reduces LCN2 expression or any combination thereof or the broad genus of neutralizing antibody/antibody to the receptor for treating or preventing brain metastases.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. The specification only describes detecting increased LCN2 protein levels in plasma and CSF isolated from melanoma and breast cancer-derived metastases-bearing mice compared to healthy mice and in blood sample isolated from human patients with brain metastasis from melanoma, breast cancer or lung carcinoma were upregulated compared with healthy controls and attenuating LCN2 protein and gliosis-related signature genes induced by melanoma conditioned medium (CM) in primary astrocytes cultured in the melanoma CM in vitro by an LCN2 neutralizing antibody or simvastatin (Example 6, figures 7A-7F). The specification provides no well-established correlation between reduction of systemic LCN2 levels in blood or circulating astrocytes in a patient with brain metastases compared to a healthy control by administration of a structurally and functionally defined anti-LCN2 neutralizing antibody to the patient and the treatment of brain metastases from different cancers in patients in vivo using the claimed LCN2 Inhibitor or agent including anti-LCN2 neutralizing antibody or antibody to the receptor.
As an initial matter, Applicant has provided no structures or sequences sufficiently detailed to show that he/she was in possession of the claimed invention as a whole. There was also no known or disclosed correlation between the required function (i.e. binding to and neutralizing LCN2) and any particular structure or sequence.
Applicant has not disclosed sufficient species for the broad genus of LCN2 inhibitor or agent or the genus of anti-LCN2 neutralizing antibodies or antibody to the receptor. The specification fails to demonstrate that Applicant is in possession of using the claimed genus of LCN2 inhibitor or agent, or anti-LCN2 neutralizing antibody or antibody to the receptor.
In light of Amgen, Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describing a “fully characterized antigen” for an antibody is no longer adequate on its own to demonstrate possession of the antibody. Based on MPEP§2161.01 and 2163, the USPTO guidance regarding written description requirement of 35 U.S.C.§C112 (a), specifically concerning the written description requirement for claims drawn to antibodies and Federal Circuit decisions, when an antibody is claimed, 35USC112(a) requires adequate written description of the antibody itself. See Amgen 872 F.3d at 1378-79.
The court of the Federal Circuit also stressed that the “newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. See Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir.2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
The specification provides no well-established structural and functional relationship between the claimed genus of LCN2 inhibitor or agent or the claimed genus of LCN2 neutralizing antibody or antibody to the receptor and the anti-LCN2 antibody disclosed in US8481032 or US7645616. The specification fails to teach what other structures/amino acid sequences can or cannot be included/changed in all LCN2 neutralizing antibody or antibody to the receptor in order to preserve the activity of LCN2 neutralizing antibody known in the art in reducing LCN2 levels in blood or circulating astrocytes or even in treating or preventing brain metastases.
The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of LCN2 inhibitor or agent or the claimed genus of LCN2 neutralizing antibody or antibody to the receptor. There is no description of the conserved regions which are critical to the function of the genus claimed. There is no information regarding the relation of structure of LCN2 inhibitor or agent or the claimed genus of LCN2 neutralizing antibody or antibody to the receptor to the function of the known anti-LCN2 neutralizing antibody disclosed in US8481032 or US7645616. Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to identify what other LCN2 inhibitors or agents or other LCN2 neutralizing antibodies or antibodies to the receptor might be. Since the common characteristics/features of other LCN2 inhibitors or agents or other LCN2 neutralizing antibodies or antibodies to the receptor are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of using the genus of LCN2 inhibitors or agents or other LCN2 neutralizing antibodies or antibodies to the receptor for treating or preventing brain metastases.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of LCN2 inhibitors or agents or other LCN2 neutralizing antibodies or antibodies to the receptor for treating or preventing brain metastases, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed method has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
8. 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 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.
Claim Rejections - 35 USC § 103
9. 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-5, 7-8 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Alt et al. (US20120219561, published Aug 30, 2012, priority Jul 31, 2009) in view of Aziz et al. (US2005/0181375, published Aug 18, 2005, priority Jan 10, 2003, as in IDS) and Arlinghaus et al. (US20080274104, published Nov 6, 2008, priority Feb 10, 2005); and evidentiary reference: Pavlou et al. (Prog. Neurobiol.2019; 174:36-52).
The rejection is based on what is enabled within the claims as set forth above under the 112(a) rejection.
Alt et al. (US20120219561) teach a method for reducing tumor or cancer metastasis, comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of an antagonist to LCN2 including an anti-LCN2 blocking antibody (as in claims 7 and 13), wherein the patient suffers from different cancers including breast cancer or lung cancer as recited in claim 8 (see abstract; Example 1, paragraphs [0036]-[0050]; claims 1-15). The limitations “systemic LCN2 signaling pathways instigate neuroinflammation”, “interferes in systemic LCN2 signaling pathway”, “suppress downstream pathways of LCN2-mediated astrocyte activation” and “suppress JAK2-STAT3 and/or Rho-ROCK” recited in claims 2-5 are the results of administration of anti-LCN2 blocking antibody as evidenced by Pavlou et al. (see p.42, Pavlou et al., Prog. Neurobiol.2019; 174:36-52).
But Alt does not teach that the cancer metastasis is brain metastasis.
Aziz et al. (US2005/0181375) teach that the expression level of lipocalin 2 (NGAL) is upregulated in breast metastases to the brain (p. 56, table 3, [0335]) and lung metastases to the brain (see [0338], Table 6A) and method of diagnosis of brain metastases from breast cancer and lung cancer (see para.[0189]-[0202]; [0211], claim 22).
Arlinghaus et al. (US20080274104) teach a method for treating different cancers including primary brain cancer, comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of an inhibitor agent including antibody, antisense or siRNA against neutrophil gelatinase-associated lipocalin (NGAL), which is called LCN2 (see abstract; paragraphs [0011]; [0019]; [0021]).
A person of ordinary skill in the art would have recognized that selecting and applying the known increased level of LCN2 protein in breast/lung-derived brain metastases, the known anti-LCN2 antibody for treating brain cancer and the known technique disclosed by Aziz and Arlinghaus to the Alt’s method would have yielded the predictable result of reducing systemic LCN2 protein in blood of patients with brain metastases derived from breast cancer or lung cancer and resulted in an improved method.
Patents with breast/lung cancer-derived brain metastases have increased levels of LCN2 protein, and an anti-LCN2 neutralizing antibody has been used for reducing cancer metastasis and treating brain cancer. Using an anti-LCN2 neutralizing antibody in patients with brain metastases in the Alt’s method would reduce the systemic LCN2 protein levels in blood or circulating astrocytes of patients with breast/lung cancer-derived brain metastases, and expand application of the Alt’s method, and would increase patient’s satisfaction with reducing cancer metastases including breast/lung cancer-derived brain metastases using an anti-LCN2 antibody.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known increased level of LCN2 protein in breast/lung-derived brain metastases, the known anti-LCN2 antibody for treating brain cancer and the known technique disclosed by Aziz and Arlinghaus to the Alt’s method and yield the predictable result of reducing the LCN2 protein levels in breast/lung cancer-derived brain metastases.
Conclusion
10. NO CLAIM IS ALLOWED.
11. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Dala et al. (WO2021137254), published July 8, 2021, priority Jan 03, 2020) teaches a method of treating LCN2 overexpression disorder or LCN2-meidaed tumor progression including different forms of cancer, melanoma, lung cancer, breast cancer….brain tumor.. and tumor metastases, comprising administering to a subject an anti-LCN2 antibody (see abstract; p.22; p. 34-37, Example 14-15; p.45, claims 15-17).
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Chang-Yu Wang
March 5, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675