DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1-14 and 17-20 with species (proteins listed in Table 3): a. one or more proteins, lipopolysaccharide-responsive and beige-like anchor protein (LRBA) in the reply filed on April 23, 2026 is acknowledged.
3. Claims 1-14, 17-20, 22 and 23 are pending.
Claims 22 and 23 drawn to non-elected inventions and species are not examined.
Claims 15, 16, 21 and 24-29 have been cancelled.
Claims 1-5, 10, 11, 22 and 23 have been amended.
Claims 1-14 and 17-20 are examined on the merits with species (proteins listed in Table 3): a. one or more proteins, lipopolysaccharide-responsive and beige-like anchor protein (LRBA).
Claim Objections
4. Claims 1 and 19 is objected to because of the following informality:
a. claim 1 cites lymphocyte antigen 75 and CD205. These terms are synonymous, hence the citation of both is superfluous. Applicant should select one of the two terms; and
b. claim 19 reads “wherein the sample is a bone marrow sample from the subject and the method further comprises obtaining a bone marrow sample from a subject”. The claim has redundant language and not further limiting.
Correction is required.
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.
6. Claims 11 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.
a. Claim 11 recites “preferably a/an CDx in the sample,” on line 2 of steps (a)-(e). This exemplary term, preferably is confusing and indefinite because the scope of the claim is not clear. It is not clear if the language following the term is an example or a preference. Accordingly, the metes and bounds cannot be determined.
Claim Rejections - 35 USC § 101
7. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
8. The claimed invention is directed to non-statutory subject matter. The claim(s) (claims 1-14 and 17-20) does/do not fall within at least one of the four categories of patent eligible subject matter because they read on a judicial (i.e., a law of nature, a natural phenomenon, or an abstract) without significantly more.
The claimed invention (claims 1-14 and 17-20) is directed to a judicial exception and/or natural phenomenon without significantly more. The claim(s) recite(s) a method of detecting multiple myeloma (MM) in a sample from an individual having or suspected of having MM based on the detected expression of protein biomarker, lipopolysaccharide-responsive and beige-like anchor protein (LRBA), additional biomarker(s) and combinations thereof expressed at a higher level in said sample than in a non-cancer control. A difference between the biomarker(s) expression and the non-cancer control expression is indicative of an individual has MM.
Furthermore, the claimed invention reads on treating MM with an anti-cancer therapy if at least one of the one or more proteins are detected at a higher level in the sample than in a non-cancer control. Selection of the anti-cancer therapy is based on the detection of a specific protein biomarker(s).
The judicial exception reads assaying a protein biomarker(s) expression level in an individual’s sample, comparing it to a non-cancer control biomarker(s) expression level and based on differences between these levels is indicative the individual has MM and treatment should commence based on the protein biomarker detected.
Moreover, anti-cancer therapy should take place if at least one or more proteins are detected at a higher level in the individual’s sample than in a non-cancer control. It is not clear how a clinician should proceed if one or more proteins is not detected or at a lower level than the non-cancer control.
This judicial exception is not integrated into a practical application because gathering information and observing the difference in candidate cancer protein biomarker(s) level(s) between an individual’s biological sample and a reference level(s) required to use the correlation does not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
The analysis as set forth in the 2019 Guidance is as follows:
Step 1: Yes, claims are drawn to a method which is one of the four statutory categories, a process.
Step 2A, prong 1: Yes, the claims recite/describe/set forth a judicial exception. The claims describe the relationship between the difference in an individual’s protein biomarker, LRBA and/or additional protein biomarker(s) and non-cancer control biomarker(s) level is indicative of the individual having or suspected of having MM, as well as the treatment to select based on the detection of a particular protein biomarker(s).
Furthermore, the decisions to render or not render treatment is conditional. “[I]f at least one of the one or more proteins are detected at a higher level in the sample than in a non-cancer control”, there is treatment intervention, see claim 10 on page 3 of the Amendments to the Claims submitted April 23, 2026. However, the claims do not provide for protein expression level that is not detected or lower than the non-cancer control, there is no direction. There are no additional elements or combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Step 2A, prong 2: No, the judicial exception is not integrated into a practical application. The claims do not rely on or use the exception here. Once differences in protein expression within the individual’s sample and a non-cancer control, there are no additional elements or combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Step 2B: There is no inventive concept present in the clams. The steps of analyzing the level of candidate cancer protein biomarker(s) in a biological sample and comparing its expression level with another is established by well understood, routine conventional methods, and in addition they are pre-solution activity, i.e. data gathering necessary to perform the correlation. The following claims and steps inform one of ordinary skilled in the art, the comparison and the level of biomarker(s) identifies an individual as requiring treatment, however remiss of an active administration step. The claims do not recite additional elements that amount to significantly more than the judicial exception. Accordingly, these claims are not be eligible under step 2A or step 2B.
Claims 1-14 and 17-20 are drawn to a non-statutory method having a "natural principle" as a limiting element or step without reciting additional elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied, and are sufficient to ensure that the claim amounts to significantly more than the natural principle itself. In the instant case, the "natural principle" is: detecting protein biomarker(s), expression protein biomarker(s) as compared to a non-cancer control and difference in biomarker levels between the individual sample and the non-cancer control level is indicative of the individual having or suspected of having MM and specific treatment.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying candidate cancer protein biomarkers, as well as their expression does not add significantly more and is not an inventive concept. Because methods for making such determinations were well known in the art, these steps simply tell researchers to engage in well-understood, routine, conventional activity previously engaged in by scientists in the field. Such activities are normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law. The claims do not add significantly more to the natural phenomenon because the claims do not require a novel reagent, apparatus of incorporate a novel treatment based on the correlation.
A claim that focuses on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Recited elements such as “detecting” based on the natural principle impose no meaningful limit on the performance of the claimed invention. As set forth the claims do not impose meaningful limits on the performance of the claimed invention. Patents cannot be obtained on subject matter identified by the courts as being exempted from eligibility (i.e., laws of nature, natural phenomenon, and abstract ideas). Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the recited natural principle. The claims do not "practically apply" the natural principle; rather, the claims "simply inform" the natural principle to one performing routine active method steps and do not amount to significantly more than the natural principle itself. Thus, the technology used by the instant claims is well-known in the art and does not contribute significantly more to the judicial exception. See the 2019 Revised Patent Subject Matter Eligibility Guidance and Federal Register https://www.federalregister.gov/documents/2019/10/18/2019-22782/october-2019-patent-eligibility-guidance-update; and FDsys.gov.
Claim Rejections - 35 USC § 102
9. 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.
10. Claim(s) 1-13 and 17-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maney et al., WO 2014/193999 A2 (published 4 December 2014). Maney discloses methods of detecting conditions or diseases by sampling proteins biological samples including bone marrow and biopsies, see page 3, sections 0015 and 0017; page 5, section 0025; page 14, section 0065; and page 21, sections 0092-0096. Multiple myeloma (MM) is a disease that can be detected with the presence of a protein biomarker within a biological sample and its level compared to a reference, see page 5, section 0025; page 6, section 0026; page 18, line 3 above section 0079; and page 19, line 7 and section 0081, line 7.
Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) within Table 5 (page 103, line 5) is a biomarker that provides diagnosis in a subject for the disease or disorder, including MM, see pages 88, section 00401. Additional protein biomarkers that may be detected, which aid in diagnosis of MM are prothrombin (page 33, section 00134; page 226, line 4); serotransferrin (page 112, line 10; page 113, line 6); thy-1 membrane glycoprotein also art known as CD90 (page 5, line before section 0022); syndecan/CD138 (page 94, line 4 before Prostate Vesicle…segment); CD5, CD147, CD166 (page 119, Cluster…segment); CD98 also art known as CD98hc and SLC3A2 (page 122, line 8 from bottom of box; line 1 on page 181); EFNB2 (page 121, Epithelial…segment; page 127, section 4); and GNPTG (page 109).
The proteins can be analyzed by mass spectrometry and flow cytometry, see page 157, section 0537.
“[A] phenotype of a subject is characterized by analyzing a biological sample and determining the presence, level, amount, or concentration of one or more populations of circulating biomarkers in the sample, e.g., circulating vesicles, proteins or nucleic acids…In some embodiments, circulating biomarkers are purified or concentrated from a sample prior to determining their amount. Unless otherwise specified, "purified" or "isolated" as used herein refer to partial or complete purification or isolation.”, see page 63, section 00261.
Maney discloses suitable anti-cancer treatments, which are able to be administered to subjects and applicable to each target protein, see Table 7 spanning pages 187-189.
Claim Rejections - 35 USC § 103
11. 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.
12. Claim(s) 1-14 and 17-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maney et al., WO 2014/193999 A2 (published 4 December 2014), and further in view of Wollscheid et al. (Nature Biotechnology 27(4): 378-386/ IDS reference 13 submitted October 9, 2024) and Krishnan et al., (Neoplasia 18(1): 25-32, 2016). Maney teaches methods of detecting conditions or diseases by sampling proteins within biological samples including bone marrow and biopsies, see page 3, sections 0015 and 0017; page 5, section 0025; page 14, section 0065; and page 21, sections 0092-0096. Multiple myeloma (MM) is a disease that can be detected with the presence of a protein biomarker within a biological sample and its level compared to a reference, see page 5, section 0025; page 6, section 0026; page 18, line 3 above section 0079; and page 19, line 7 and section 0081, line 7.
Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) within Table 5 (page 103, line 5) is a biomarker that provides diagnosis in a subject for the disease or disorder, including MM, see pages 88, section 00401. Additional protein biomarkers that may be detected, which aid in diagnosis of MM are prothrombin (page 33, section 00134; page 226, line 4); serotransferrin (page 112, line 10; page 113, line 6); thy-1 membrane glycoprotein also art known as CD90 (page 5, line before section 0022); syndecan/CD138 (page 94, line 4 before Prostate Vesicle…segment); CD5, CD147, CD166 (page 119, Cluster…segment); CD98 also art known as CD98hc and SLC3A2 (page 122, line 8 from bottom of box; line 1 on page 181); EFNB2 (page 121, Epithelial…segment; page 127, section 4); and GNPTG (page 109).
The proteins can be analyzed by mass spectrometry and flow cytometry, see page 157, section 0537.
“[A] phenotype of a subject is characterized by analyzing a biological sample and determining the presence, level, amount, or concentration of one or more populations of circulating biomarkers in the sample, e.g., circulating vesicles, proteins or nucleic acids…In some embodiments, circulating biomarkers are purified or concentrated from a sample prior to determining their amount. Unless otherwise specified, "purified" or "isolated" as used herein refer to partial or complete purification or isolation.”, see page 63, section 00261.
Maney teaches suitable anti-cancer treatments, which are able to be administered to subjects and applicable to each target protein, see Table 7 spanning pages 187-189.
Maney does not teach the proteins are detected by cell surface capture (CSC) or parallel reaction monitoring (PRM) assay. Nor does, Maney teach the taught method comprises isolating CD138+ cell from the sample prior to detecting the one or more proteins.
However, Wollscheid teaches cell surface-capturing (CSC) technology utilizing “…uses a multistep tandem affinity labeling strategy to confer the desired specificity for the glycoproteins on the cell surface.”, thereby permitting “…comprehensive and quantitative analysis of the cell surface glycoprotein landscape at very high specificity. “, see Figure 1 on page 379 and the 1st column (col.), 2nd paragraph (para.). And Krishnan teaches the isolation of human CD138+ microparticles (MPs) from a MM patient’s biological sample, see entire document. Elevated levels of CD138 in the biological samples of MM patients is known to yield a deleterious prognosis in MM patients, see para. bridging pages 30 and 31; and last para. before Acknowledgments.
Hence, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize CSC technology to further measure, quantify, distinguish and differentiate glycoproteins, including CD138, a hallmark for MM diagnosis and candidate cancer protein biomarker(s).
One of ordinary skill in the art would have been motivated to
integrate, combine and implement the teachings of Maney, Wollscheid and Krishnan to sample and isolate different protein biomarkers, such as CD138 with the aid of CSC technology to define the MM protein biosignature. The expression of this protein “…correlates with therapeutic response…” and CD138+ MPs are increased in MM. One of ordinary skill in the art would have been motivated to use CSC technology given it is able “…to phenotype cells without antibodies in an unbiased fashion and with a priori knowledge.”, see Wollscheid abstract and entire document, as well as the entirety of all references.
Conclusion
13. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
- Oldham et al. Discovery and validation of surface N-glycoproteins in MM cell lines and patient samples uncovers immunotherapy targets. Journal for ImmunoTherapy of Cancer. 8(3): 1-12, 7 August 2020.
14. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday.
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, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
10 June 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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