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 .
Drawings
The drawings were received on 4/25/2024. These drawings are acceptable.
Claim Rejections - 35 USC § 112
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 13 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 is drawn to “the method of diagnosing LM of claim 12” but claim 12 is directed to a method of treating LM. Clarification is requested as to the correct dependency of claim 13.
Claim 20 is drawn to “the method of diagnosing LM of claim 14” but claim 14 is directed to a method of treating LM. Clarification is requested as to the correct dependency of claim 20.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1-3, 5, and 11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kang et al., “Diagnostic Value of Cerebrospinal Fluid Level of Carcinoembryonic Antigen in Patients with Leptomeningeal Carcinomatous Metastasis”, Journal of Clinical Neurology, 2010, Vol. 6, pp. 33-37 (provided by applicant in IDS dated 4/25/2024).
With respect to claim 1 Kang discloses a method of diagnosing leptomeningeal metastasis (LM) of a cancer in a subject comprising:
a) obtaining a biological sample (See abstract for discussion of multifocal seeding of the leptomeninges by malignant cells, which is usually referred to as leptomeningeal carcinomatous metastasis, produces substantial morbidity and mortality. The diagnosis of leptomeningeal metastasis is usually established by cerebrospinal fluid (CSF) investigation; See Pg. 35, Col 1., Para. 4: 'CSF samples (3 ml) were collected for the tests.'); and
b) obtaining blood chemistry measurements in the biological sample (See Abstract for discussion of the diagnosis of leptomeningeal metastasis being established by cerebrospinal fluid (CSF) investigation, including cytology, cell counts, protein, glucose, and a tumor marker such as carcinoembryonic antigen (CEA)... CSF CEA level was measured in 32 patients with leptomeningeal metastasis);
wherein a significant deviation of one or more measurements relative to the same measurements from a nonmetastatic control indicates the presence of LM (See Abstract, "This study examined the diagnostic value of CEA in the CSF .... We measured the CSF CEA level in 32 patients with leptomeningeal metastasis. The control group consisted of 19 cancer patients without leptomeningeal metastasis. CEA was measured by the chemiluminescent emission method.... The level of CSF protein was higher and that of CSF glucose was lower in patients with leptomeningeal metastasis than in the control group ... The CSF CEA level is useful for diagnosing leptomeningeal carcinomatous metastasis. The CSF levels of protein and glucose are also useful in the diagnosis.").
With respect to claim 2 Kang discloses that the biological sample comprises cerebrospinal fluid (CSF) (See abstract).
With respect to claim 3 Kang discloses that the one or more blood chemistry measurement comprises a measurement of Glucose (Glu) (See abstract).
With respect to claim 5 Kang discloses that a lower glucose indicates LM (See abstract).
With respect to claim 11 Kang discloses that the cancer comprises breast cancer or lung cancer (See Pg. 354, Col. 2, Para. 2, “In the metastasis group, stomach cancer was most common, followed by lung cancer, breast cancer, esophageal cancer, and cholangiocarcinoma.")
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.
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(s) 12-14 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kang et al., “Diagnostic Value of Cerebrospinal Fluid Level of Carcinoembryonic Antigen in Patients with Leptomeningeal Carcinomatous Metastasis”, Journal of Clinical Neurology, 2010, Vol. 6, pp. 33-37 (provided by applicant in IDS dated 4/25/2024).
With respect to claim 12 Kang discloses a method of diagnosing LM in a subject comprising:
a) obtaining a biological sample (Abstract);
b) obtaining a blood chemistry measurements in the biological sample (Abstract): wherein a significant deviation of one or more measurements relative to the same measurements from a nonmetastatic control indicates the presence of LM (See Abstract).
Kang fails to disclose treating LM, wherein the method further comprises c) administering to the subject anti-cancer therapy.
Kang teaches use of serum CEA during follow-up after cancer treatment (See Pg. 36, Col. 1, Para. 2 - 'It is also useful during follow-up after cancer treatment,').
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow up a diagnosis of LM with anti-cancer therapy (See Pg. 36, Col. 1, Para. 2 of Kang), as treating a subject following cancer diagnosis by administration of an appropriate treatment is well known in the art.
With respect to claim 13 Kang teaches that the biological sample comprises cerebrospinal fluid (CSF) (See abstract).
With respect to claim 14 Kang teaches that he one or more blood chemistry measurements comprise a measurement of Glucose (Glu) (See abstract).
With respect to claim 21 Kang teaches that the cancer comprises breast cancer or lung cancer (See Pg. 34, Col. 2, Para. 2 - "In the metastasis group, stomach cancer was most common, followed by lung cancer, breast cancer, esophageal cancer, and cholangiocarcinoma").
Claim(s) 6 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kang et al., “Diagnostic Value of Cerebrospinal Fluid Level of Carcinoembryonic Antigen in Patients with Leptomeningeal Carcinomatous Metastasis”, Journal of Clinical Neurology, 2010, Vol. 6, pp. 33-37 in view of Scheffer et al., “Identification of Further Components of an Anticancer Defense System Composed of Small Molecules Present in the Serum”, Cancer Biotherapy and Radiopharmaceuticals”, 2019, Vol. 34, No. 3, pp. 160-170 (provided by applicant in IDS dated 4/25/2024).
Refer above for the disclosure and teachings of Kang.
With respect to claim 6 Kang fails to disclose that the keto acid levels measured are 3- methyl/4-methyl-2-oxovaleric acid and 3-methyl-2-oxobutanoic acid.
Scheffer teaches wherein the presence of keto acids play a role in the prevention of cancer progression (See Abstract - "Earlier we assumed that small molecules selectively accumulated in cancer cells might have a role in a defense system capable of killing cancer cells. We reported earlier that an experimentally selected mixture of substances present in the serum ("active mixture," AM) shows a selective toxic effect in vitro and in vivo on various cancer cells. In this study we investigated additional compounds found in the serum to further expand our knowledge of this defense system.... The newly identified compounds significantly enhance the anticancer effect of AM. The components of AM and NM together may form part of a defense system capable of killing cancer cells and are worthy of further investigation"; See Pg. 167, Col. 2, Para. 1 – “The components of NM are mainly I-amino acid metabolites, phenolic acids (benzoic acid derivatives, cinnamic acid derivatives), d-amino acids, and keto acids. Some of these newly identified compounds have been reported to have anticancer activities'). Among the keto acids Scheffer teaches that the keto acids 3- methyl/4-methyl-2-oxovaleric acid and 3-methyl-2-oxobutanoic acid are advantageous (See Pg. 161, Col. 2, Para. 2 - "The composition of the 100% NM, identified in this article, is as follows...2.5 mM 3-methyl-2-oxovaleric acid sodium salt, 3 mM 4-methyl-2-oxovaleric acid sodium salt...3-methyl-2-oxobutyric acid sodium salt").
it would have been obvious to one of ordinary skill in the art before the effective filing date to consider 3- methyl/4-methyl-2- oxovaleric acid and 3-methyl-2-oxobutanoic acid as markers of cancer progression or susceptibility, given the role that they each play in cancer prevention, as taught by Scheffer, and thus it would have been obvious to determine through routine experimentation their relation to metastasis when present in serum or other bodily fluid samples as additional biomarkers for the method of Kang (See Pg. 167, Col. 2, Para. 1 of Scheffer).
With respect to claim 20 Kang fails to teach that the keto acid levels measured are 3- methyl/4-methyl-2-oxovaleric acid and 3-methyl-2-oxobutanoic acid.
Scheffer teaches wherein the presence of keto acids play a role in the prevention of cancer progression (See Abstract - "Earlier we assumed that small molecules selectively accumulated in cancer cells might have a role in a defense system capable of killing cancer cells. We reported earlier that an experimentally selected mixture of substances present in the serum ("active mixture," AM) shows a selective toxic effect in vitro and in vivo on various cancer cells. In this study we investigated additional compounds found in the serum to further expand our knowledge of this defense system....The newly identified compounds significantly enhance the anticancer effect of AM. The components of AM and NM together may form part of a defense system capable of killing cancer cells and are worthy of further investigation"; See Pg. 167, Col. 2, Para. 1 – “The components of NM are mainly I-amino acid metabolites, phenolic acids (benzoic acid derivatives, cinnamic acid derivatives), d-amino acids, and keto acids. Some of these newly identified compounds have been reported to have anticancer activities'). Among the keto acids Scheffer teaches that the keto acids 3- methyl/4-methyl-2-oxovaleric acid and 3-methyl-2-oxobutanoic acid are advantageous (See Pg. 161, Col. 2, Para. 2 - "The composition of the 100% NM, identified in this article, is as follows...2.5 mM 3-methyl-2-oxovaleric acid sodium salt, 3 mM 4-methyl-2-oxovaleric acid sodium salt...3-methyl-2-oxobutyric acid sodium salt").
it would have been obvious to one of ordinary skill in the art before the effective filing date to consider 3- methyl/4-methyl-2- oxovaleric acid and 3-methyl-2-oxobutanoic acid as markers of cancer progression or susceptibility, given the role that they each play in cancer prevention, as taught by Scheffer, and thus it would have been obvious to determine through routine experimentation their relation to metastasis when present in serum or other bodily fluid samples as additional biomarkers for the method of Kang (See Pg. 167, Col. 2, Para. 1 of Scheffer).
Claim(s) 7-10 and 16-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kang et al., “Diagnostic Value of Cerebrospinal Fluid Level of Carcinoembryonic Antigen in Patients with Leptomeningeal Carcinomatous Metastasis”, Journal of Clinical Neurology, 2010, Vol. 6, pp. 33-37 in view of Grobe et al (US 2018/0228806 A1) (provided by applicant in IDS dated 4/25/2024).
Refer above for the disclosure and teachings of Kang.
With respect to claim 7 Kang fails to disclose that the one or more blood gas, blood chemistry, or hematological measurements are obtained using a point-of-care body fluid analyzer.
Grobe teaches a point-of-care body fluid analyzer for detecting blood chemistries (See Para. 0127 - "Blood chemistries and urine creatinine were determined using a handheld iSTAT clinical chemistry analyzer (Abbott), with CHEM8+ cartridges").
Given the availability of point-ofcare blood chemistry analyzers, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use a known method of collecting and analyzing a sample from a patient, such as the point-of-care methods taught by Grobe.
With respect to claim 8, the combination of Kang and Grobe teaches that the blood measurements are on a cartridge for use with a body fluid analyzer (See Para. 0127 of Grobe).
With respect to claim 9, the combination of Kang and Grobe teaches that the point of care body fluid analyzer is an iSTAT (See Para. 0127 of Grobe).
With respect to claim 10, the combination of Kang and Grobe teaches the method that the one or more blood gas, blood chemistry, or hematological measurements are on a CHEM8 or CG4 cartridge (See Para. 0127 of Grobe).
With respect to claims 16 and 17 Kang fails to teach that the one or more blood gas, blood chemistry, or hematological measurements are obtained using a point-of-care body fluid analyzer.
Grobe teaches a point-of-care body fluid analyzer for detecting blood chemistries (See Para. 0127 - "Blood chemistries and urine creatinine were determined using a handheld iSTAT clinical chemistry analyzer (Abbott), with CHEM8+ cartridges").
Given the availability of point-ofcare blood chemistry analyzers, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use a known method of collecting and analyzing a sample from a patient, such as the point-of-care methods taught by Grobe.
With respect to claim 18, the combination of Kang and Grobe teaches that the point of care body fluid analyzer is an iSTAT (See Para. 0127 of Grobe).
With respect to claim 19, the combination of Kang and Grobe teaches the method that the one or more blood gas, blood chemistry, or hematological measurements are on a CHEM8 or CG4 cartridge (See Para. 0127 of Grobe).
Claim(s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kang et al., “Diagnostic Value of Cerebrospinal Fluid Level of Carcinoembryonic Antigen in Patients with Leptomeningeal Carcinomatous Metastasis”, Journal of Clinical Neurology, 2010, Vol. 6, pp. 33-37 in view of Lu, N.T., Raizer, J., Gabor, E.P. et al. Intrathecal trastuzumab: immunotherapy improves the prognosis of leptomeningeal metastases in HER-2+ breast cancer patient. j. immunotherapy cancer 3, 41 (2015). https://doi.org/10.1186/s40425-015-0084-y (hereinafter referred to as Lu).
Refer above for the disclosure and teachings of Kang.
With respect to claim 22 Kang fails to teach that the anti-cancer therapy comprises radiation therapy, intrathecal chemotherapy, or immunotherapy.
Lu teaches the clinical and therapeutic course of a 51-year-old woman with HER-2+ breast cancer who developed leptomeningeal (LM) and spinal cord metastases after 8 years of stable disease on combination therapy with intravenous (IV) trastuzumab. Due to progressive CNS disease, intrathecal (IT) trastuzumab was introduced to enhance HER-2+ therapy into the CSF space. A combination HER-2+ targeted approach achieved clinical remission with stable disease in our patient 46 months after she was diagnosed with LM metastases. However, spinal cord C-1 metastasis was not fully controlled with IT trastuzumab, ultimately leading to the patient’s respiratory compromise. In our patient, IT trastuzumab immunotherapy improved prognosis and was an effective strategy to manage HER-2+ LM disease. Given alone or alongside other anti-HER-2+ therapeutics with sufficient CNS penetration, IT trastuzumab could extend the lifespan of patients with leptomeningeal and CNS metastases (See abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize immunotherapy as anti-cancer therapy for the method of Kang, as taught by Lu, given that IT trastuzumab immunotherapy has demonstrated improved prognosis and extension of the lifespan of patients with leptomeningeal and CNS metastases (See abstract of Lu).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRITTANY I FISHER whose telephone number is (469)295-9182. The examiner can normally be reached IFP.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Lin can be reached at (571) 272-8902. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRITTANY I FISHER/Examiner, Art Unit 1796 August 21, 2026
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