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 .
Amendment Entry
1. Applicant’s response to the Non-Final Action mailed May 1, 2025 is acknowledged (paper filed 9/1/25 & 12/18/25). In the amendment filed therein new claims 17 and 18 were added. Claims 2 and 12-14 were canceled without prejudice or disclaimer. Currently, claims 1, 3-11, and 15-18 are pending and under consideration.
2. Objections and/or rejections of record not reiterated therein have been withdrawn.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the Examiner on form PTO-892 or Applicant on PTO-1449 cited the references they have not been considered.
4. The Information disclosure Statements (IDS) filed on 10/24/25 has been considered as to the merits before Final Action.
Priority
5. This application has a priority date of 5/23/17: This application is the National Phase Under 35 USC § 371 of PCT International Application No. PCT/GB2018/051401 filed on May 23, 2018, which claims priority under 35 U.S.C. § 119 on Patent Application No. 1708262.9 filed in the United Kingdom on May 23, 2017.
NEW GROUNDS OF REJECTIONS NECESSITATED BY AMENDMENTSClaim Rejections - 35 USC § 103
6. 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.
7. Claims 1, 3-11, and 15-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Harding et al. (WO 2013/132245 A1) in view of Bradwell et al. (WO2011/114250A1) and further in view of Francesca Lavatelli et al. (Biochimica et Biophysica Acta (BBA) -PROTEINS & PROTEOMICS, ELSEVIER, NETHERLANDS, vol. 1814, no. 3, 28 December 2010 (2010-12-28), pages 409-419) and Campbell et al. (Journal of Immunological Methods, 391, 2013, pages 1-13).
Harding et al. disclose a method for detecting a plasma cell associated disease in a patient comprising: (i)providing at least one sample from the patient; (ii)determining in the sample(s) two or more of; (a) the κ:λ free light chain (FLC) ratio; (b) the ratio of κ light chains bound to a class of heavy chain :
λ light chain bound to the same class of heavy chain (HLC κ : HLC λ ratio); (c) the total amount of FLC in the samples and (d) the total amount of κ light chains bound to the heavy chain class plus λ light chains bound to the same heavy chain class (total HLC); (iii)comparing each ratio or amount from (a) (b), (c) and/or (d) to predetermined values and assigning a score to each amount or ratio; and (iv)using the scores to measure the plasma cell associated disease. See abstract.
Harding et al. also disclose that antibodies, or fragments of antibodies, specific for or λ FLC are generally know and are commercially available under the trade name Freelite™. See page 16.
The plasma cell associated disease may be a monoclonal gammopathy. It may be B-cell associated diseases such as myeloma, (such as intact immunoglobulin myeloma, light chain myeloma, non-secretory myeloma), an MGUS, AL amyloidosis, Waldenstrom's macroglobulinaemia, Hodgkin's lymphoma, follicular centre cell lymphoma, chronic lymphocytic leukaemia, mantle cell lymphoma, pre-B cell leukaemia or acute lymphoblastic leukaemia. The plasma cell associated disease may also be a polyclonal associated disease such as hypergammaglobulineamia or hypogammaglobulineamia. Page 6.
Although Harding et al. detect both anti-kappa FLC and anti-lambda FLC in their patient samples, Harding et al. differ from the instant invention in not specifically reciting that a mixture of anti-kappa FLC and anti-lambda FLC are contacted with the sample. See claims 1 and 16 (i and ii).
However, Bradwell et al. (WO 2011/114150) teach this limitation. Bradwell et al. disclose methods and kits for identifying a subject likely to have liver disease, or for determining the prognosis of a subject previously identified as having a liver disease wherein the method detects an amount of free light chains (FLC) in a sample from the subject. And a higher amount of FLC is associated with an increased likelihood of the subject having a liver disease or an increased likelihood of having a poor prognosis of a liver disease. See abstract.
In one embodiment the kit employs a mixture of anti-κ and anti-λ FLC antibodies. The kit is utilized to measure free light chains in the sample. See page 8 lines 5-8 and pages 10-13.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to employ a mixture of anti-κ and anti-λ FLC antibodies as taught by Bradwell et al. in the method of Harding et al. measuring free FLC antibodies because Bradwell demonstrated that the combined anti-κ/anti-λ FLC antibody mixture was viable in assay procedures. See page 13. In fact, the method reduced steps (one incubation with both antibodies simultaneously verse two separate incubations of each antibody alone) and FLC are sensitive markers for immune activation in liver disease and may be useful for diagnosing and monitoring inflammatory immune mediated liver disease patients. See page 12.
Harding et al. in view of Bradwell et al. differ from the instant invention in not specifically detecting the measurement of anti-FLC specific antibodies in the sample.
However, Lavatelli et al., see especially pages 410-411, discloses an immunopurification approach to isolate serum FLC from patients with
monoclonal gammopathies, followed by proteomic characterization. Serum
monoclonal FLC were detected and quantified by immunofixation and
immunonephelometry. Immunoprecipitation was performed by serum
incubation with agarose beads covalently linked to polyclonal anti-kappa or
lambda FLC antibodies. Isolated FLC were analyzed by SDS-PAGE, 2D-
PAGE, immunoblotting and mass spectrometry (MS).
The study shows the feasibility of capture and proteomic analysis of serum FLC, and grants the extension and validation of the method on a wider population of individuals with characterized monoclonal gammopathies. See conclusion.
While, Campbell et al. teach the reagents required by the instant kit claims. The researchers describe an improved method using specific mouse anti-human FLC monoclonal antibodies (mAbs). Anti-κ (anti-kappa) and anti-λ (anti-lambda) FLC (free light chain) mAbs were, separately, covalently coupled to polystyrene Xmap® beads (or mass spectrometry target) and assayed, simultaneously, in a multi-plex format by Luminex® (mAb assay).
The mAbs displayed no cross-reactivity to bound LC, the alternate LC type, or other human proteins and had improved sensitivity and specificity over immunofixation electrophoresis (IFE) and Freelite™.
The assay gives good linearity and sensitivity (<1 mg/L), and the competitive inhibition format gave a broad calibration curve up to 437.5 mg/L and prevented anomalous results for samples in antigen excess i.e. high FLC levels. The mAbs displayed good concordance with Freelite™ for the quantitation of normal polyclonal FLC in plasma from healthy donors (n = 249). The mAb assay identified all monoclonal FLC in serum from consecutive patient samples (n = 1000; 50.1% with monoclonal paraprotein by serum IFE), and all FLC in a large cohort of urine samples tested for Bence Jones proteins (n = 13090; 22.8% with monoclonal κ, 9.0% with monoclonal λ, and 0.8% with poly LC detected by urine IFE). Importantly this shows that the mAbs are at least close to the ideal of detecting FLC from all patients and neoplastic plasma cell clones . See abstract and Discussion.
KSR forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See recent Board decision Ex parte Smith,— USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007)(citing KSR, 82 USPQ2d at 1396).
Therefore it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to measure anti-FLC specific antibodies as taught by Francesca Lavatelli et al. and Campbell et al. in the FLC purification and characterization to plasma cell associated disease as exemplified by Harding et al. in view of Bradwell et al. because Lavatelli et al. taught that their study shows the feasibility of capture and proteomic analysis of serum FLC, and grants the extension and validation of the method on a wider population of individuals with characterized monoclonal gammopathies. See conclusion.
And Campbell et al. taught that their technique was an improved method using specific mouse anti-human FLC monoclonal antibodies (mAbs). Anti-κ (anti-kappa) and anti-λ (anti-lambda) FLC (free light chain) mAbs were, separately, covalently coupled to polystyrene Xmap® beads (or mass spectrometry target) and assayed, simultaneously, in a multi-plex format by Luminex® (mAb assay).
One skilled in the art would have been motivated to identify and treat the patients diagnosed with metastatic disease as a means for prolonging the patient’s life.
Response to Arguments
8. Applicant’s arguments and amendments in the reply filed 9/1/25 with respect to the rejection(s) of claim(s) 1, 3-11, and 15-16 under 35 USC 103 over Harding et al. in view of Bradwell et al. and further in view of Francesca Lavatelli et al. and Campbell et al. have been fully considered but were not found persuasive.
More specifically, Applicant contends that the current invention does not require separate kappa and lambda FLCs to be quantified. It instead relies on the single detection of an increased peak compared to the background FLC production. This allows, for example, great sensitivity to be achieved to identify non-secretary multiple myelomas and AL amyloidosis. It also allows the FLCs to be determined without reducing intact immunoglobulins to release light chains bound to heavy chains. (quoting paragraph [0028])Therefore, the rejection has been withdrawn.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., methods without FLC digestion, wherein a ratio is not detected, therein allowing for the measurement of a monoclonal peak of a single monoclonal gammopathy via mass spectrometry) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Accordingly, the rejection is maintained.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant’s arguments against Harding et al. are not persuasive since Harding is cited in combination with Bradwell et al., Francesca Lavatelli et al., and Campbell et al.
In response to applicant's argument that Harding et al. do not teach a mixture of anti-κ and anti-λ FLC antibodies, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
Applicant argues that Harding does not teach a mixture of anti-κ and anti-λ FLC antibodies or mass spectrometry analysis. This argument was not found persuasive because the reference to Bradwell et al. (WO2011/114150) teaches these limitations. For example see pages 2, 7 8, and 9.
9. Claims 17 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sepiashvili et al. (Clinical Chemistry, 2016, Vol.62, No.10, Suppl. 1, page S5 - Abstract).
Sepiashvili et al. discloses that monoclonal free light chains (FLCs) play an important supportive role in diagnosis, prognosis, and monitoring of monoclonal gammopathies. FLCs are secreted in larger quantities by abnormal plasma cells undergoing clonal expansion. And quantitative immuno-nephelometric serum FLC (sFLC) assays are used to measure concentrations of circulating kappa (K) and lambda (L) chains unbound to their heavy chains. An abnormal K/L FLC ratio can indicate a low abundance monoclonal clone which is typically undetected by serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE). Patients with nonsecretory multiple myeloma, light chain multiple myeloma, primary systemic amyloidosis and light chain deposition disease often are only detected by the FLC ratio. On the other hand, hypergammaglobulinemia patients can also present with abnormal FLC ratios.
Therefore there is a need to directly detect monoclonal FLCs independent of the K/L ratio. To that end the researchers have developed a sensitive technique that uses nanobody enrichment-coupled with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) for detection of monoclonal proteins in serum.
The method collected residual patient serum specimens (n=48) that were negative by IFE and displayed an abnormal FLC ratio (K/L 1.65) for analysis. Nanobody enrichment was performed with CaptureSelect® affinity resins to purify IgG, IgM, IgA, K light chains and L light chains. Specimens were reduced to dissociate heavy and light chains. Additionally, FLCs were affinity purified with sepharose beads conjugated with polyclonal antibodies used for the sFLC assay (n=31), which have been shown to have high specificity towards FLCs and low cross-reactivity with light chains bound to heavy chains. Purified specimens were subjected to MALDI-TOF MS in automated acquisition mode (Bruker Microflex). FlexAnalysis software was used to interrogate spectra for isotypes and the molecular masses of monoclonal proteins. Monoclonal abnormalities were detected in 14 (29%) of nanobody-purified serum samples analyzed by MALDI-TOF MS, thereby supporting positivity by the sFLC assay. See abstract.
Sepiashvili et al. differ from the instant invention in not specifically reciting that a mixture of kappa and lambda FLCs were analyzed. However, the reference teaches that nanobody enrichment was performed with CaptureSelect® affinity resins to purify IgG, IgM, IgA, K light chains and L light chains. See abstract.
However, a long line of cases have demonstrated that it is obvious to combine prior art elements according to known methods to yield predictable results. See MPEP 2143. In this case, the prior art employs the same starting material recited in the claims (antibody detection/enrichment of lambda and kappa FLC). And their utility in plasma cell associated disease. Although Sepiashvili et al. are silent regarding a method of analyzing the purified FLC (lambda, kappa, etc.) in a single method or individual methods is deemed obvious absent evident to the contrary. It would have been prima facie obvious to conduct a single assay in order to quickly conduct said analysis, therein reduce time and reagents that are needed in multiple assay techniques.
The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In re Ochiai, 71 F.3d 1565, 37 USPQ2d 1127 (Fed. Cir. 1995) and In re Brouwer, 77 F.3d 422, 37 USPQ2d 1663 (Fed. Cir. 1996) addressed the issue of whether an otherwise conventional process could be patented if it were limited to making or using a nonobvious product. In both cases, the Federal Circuit held that the use of per se rules is improper in applying the test for obviousness under 35 U.S.C. 103. Rather, 35 U.S.C. 103 requires a highly fact-dependent analysis involving taking the claimed subject matter as a whole and comparing it to the prior art.
"A process yielding a novel and nonobvious product may nonetheless be obvious; conversely, a process yielding a well-known product may yet be nonobvious." TorPharm, Inc. v. Ranbaxy Pharmaceuticals, Inc., 336 F.3d 1322, 1327, 67 USPQ2d 1511, 1514 (Fed. Cir. 2003).
10. For reasons aforementioned, no claims are allowed.
11. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lisa Cook whose telephone number is 571-272-0816.
The examiner works a flexible schedule but can normally be reached on Monday-Friday from 9am to 5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached at telephone number 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Lisa V. Cook
Patent Examiner
Art Unit 1642
Remsen
571-272-0816
1/28/26
/LISA V COOK/Primary Examiner, Art Unit 1642