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 .
NON-FINAL ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/18/26 has been entered. A Petition to Revive was filed in the RCE dated 2/18/26. The petition was Granted on 4/14/26.
Power of Attorney
2. On 4/21/26, The Power of Attorney was accepted for:
KLARQUIST SPARKMAN, LLP
121 SW SALMON STREET
SUITE 1600
PORTLAND, OR 97204
3. On 4/21/26, The Power of Attorney was revoked for: INTELINK LAW GROUP, PC.
4. The following outstanding action is pending in the application:
Election/Restrictions
5. Applicant's election with traverse of Species (A-II claims 22 and 23) and (B-IV claims 19-21) in the reply filed on 4/28/25 is acknowledged. The traversal is on the ground(s) that no serious burden exists to examine all the claims together. More specifically, Applicant argues that there is no undue burden and the Examiner must examine all the claims on the merits, even though they include claims to independent and distinct inventions. This argument was carefully considered and not found persuasive because the inventions are independent and distinct as set forth in the Restriction Requirement mailed 2/27/25.
With respect to a different field of search — Because the inventions are distinct and have acquired separate status in the art as shown by their different classification, recognized divergent subject matter and because the search required for each invention is not substantially coextensive with the search required for the remaining invention, restriction for examination purposes as indicated is proper. Restriction is only proper when there would be a serious burden as evidenced by separate classification, status, or field of search even though the claims include independent or distinct inventions (MPEP 808.02).
Please note that the classifications in the restriction are illustrative only and do not represent all the classes and subclasses, which must be searched for each invention; nor is the search limited to issued US patents, but rather includes published foreign patents and applications as well as literature search. For these reasons the inventions were not rejoined.
6. The requirement is still deemed proper and is therefore made FINAL.
7. Claims 13, 15, and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 4/28/25.
8. Currently claims 12 and 17-25 are under consideration.
Amendment Entry
9. Applicant’s reply to the Non-Final Action mailed 6/10/24 is acknowledged (responses on 11/11/24 & 4/28/25). In the amendments filed therein claims 12 and 13 were modified. While claims 14-25 were added.
Priority
10. This application is a Divisional application of co-pending Application No. 16/615,814 which was filed on November 21, 2019, which 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.
Information Disclosure Statement
11. 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 form PTO-1449 lists the references, they have not been considered. See references listed throughout the disclosure.
12. The information disclosure statements filed 1/23/25 and 4/10/25 have been considered as to the merits prior to Final Action on the Merits.
NEW GROUNDS OF REJECTIONS NECESSITATED BY AMENDMENTS
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.
13. Claims 12, and 17-25 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.
A. Claim 12 recites the phrase "fragment(s) thereof and antibodies thereof”, however it is unclear how to define fragments and/or partial peptides that are considered to relate to the recited compositions in the instantly claimed kits. The specification does not teach examples of the required components of the recited "fragment(s) thereof and antibodies thereof” that contain conserved regions allowing for the claimed detection procedure or operation of the claimed kit. The phrase "fragment(s) thereof and antibodies thereof” are vague and indefinite because the characteristics needed to determine whether an unknown could be considered immunologically detectable or have specific binding characteristics while being "fragment(s) thereof and antibodies thereof” is unknown. In addition, an initial sequence is not recited in the claims. Accordingly the claims are unclear.
B. Claims 17-19, 21, 23,and 25 recites the limitation "anti-free light chain" in claim 12. There is insufficient antecedent basis for this limitation in the claim. Claim 12 reads on “anti-free lambda light chain” or “anti-free kappa light chain”. It is suggested that consistent language is employed in the claims to remove any ambiguity. Appropriate correction is required.
C. Claim 20 recites the limitation “non-disulphide crosslink” in claim 18. There is insufficient antecedent basis for this limitation in the claim.
DECLARATION
14. The Declaration under 37 CFR 1.132 filed by Dr Hughes is sufficient to overcome the rejection of claims 12 and 17-25 based upon 35 USC § 112(a) – written description and 35 USC § 101.
The Declaration noted that anti-FLC antibodies useful in the presently claimed method were per se known in the art, were available to a POSITA and could be readily made by a POSITA without any undue experimentation. Therefore, Dr. Hughes concludes that "the inventors had possession of the invention, at the time of filing, as defined in the present claims of the invention." (See paragraph 19) Further, the Hughes Declaration argues that in 1985 anti-human free light chain-specific antibodies were raised in rabbits. Further detailed descriptions of how anti-free light chain specific antibodies are made can be found in US Patent 8,133,744 (also cited in the Declaration) and the claimed kit therefore does not contain naturally occurring free light chains but, rather, antibodies against those free light chains, which do not occur in nature without human intervention.
In addition, the present claims are directed to a kit comprising antibodies including a mass spectrometry plate. Accordingly the rejections were withdrawn.
Claim Rejections - 35 USC § 103
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.
15. Claims 12 and 17 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 Foster (U.S. Patent #4,444,879).
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.
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.
While, Foster et al. (U.S. Patent #4,444,879) teach kit embodiments that include the reactant reagents, a microplate, positive controls, negative controls, standards, and instructions. The reagents are compartmentalized or packaged separately for utility. See figure 6, and column 15, lines 10-34.
It would have been prima facie obvious to one of ordinary skill in the art at the effective filing date of applicant’s invention to take the detection assay reagents as taught by Harding et al. in view of Bradwell and format them into a kit because Foster et al. teach that it is convenient to do so and one can enhance sensitivity of a method by providing reagents as a kit.
Further, the reagents in a kit are available in pre-measured amounts, which eliminates the variability that can occur when performing the assay. Kits are also economically beneficial in reagent distribution.
16. Claim(s) 22-23 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 Foster (U.S. Patent #4,444,879) as applied to claims 12 and 17 above, and further in view of Campbell et al. (Journal of Immunological Methods, 391, 2013, pages 1-13).
Please see Harding et al. in view of Bradwell et al. and further in view of Foster as set forth above.
Harding et al. in view of Bradwell et al. and further in view of Foster fail to teach anti-free antibody immobilization on magnetic beads.
However, 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 immobilize the reagents exemplified by Harding et al. in view of Bradwell et al. and Foster on beads because 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 plates) and assayed, simultaneously, in a multi-plex format by Luminex® (mAb assay).
17. Claim(s) 18-21 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 Foster (U.S. Patent #4,444,879) as applied to claims 12 and 17 above, and further in view of Raghuwanshi et al. (WO 2016/063299) and Goldenberg et al (Bioconjugate Chemistry, 1991, Vol. 2, pp. 275-289).
Please see Harding et al. in view of Bradwell et al. and further in view of Foster as set forth above.
Harding et al. in view of Bradwell et al. and further in view of Foster fail to teach anti-free antibodies raised in animal models such as goats wherein the antibodies are cross linked.
However, Raghuwanshi et al teach an example of an immunoaffinity purification using a goat polyclonal antibody (paragraph [0007]). Thus, it would have been prima facie obvious to use goat polyclonal anti-Ig in the immunopurification process as a routine selection previously taught by the prior art.
Regarding the polyclonal population wherein at least 70% of the antibodies comprise one or more non-reducible thioether containing cross-links between the heavy chain and the light chain replacing the naturally occurring disulphide bonds, Goldberg et al teach that the extensiveuse of antibody-containing affinity columns for the purification of biologically active compounds such as genetically engineered is severely hampered by the leaching of portions of the antibody from the immunoaffinity resin during elution of the target (abstract). Goldberg et al teach that hydrolysis of the immobilized antibody light and/or heavy chains which then contaminate the affinity purified product (page 275, lines 1-6 of the second paragraph under “Introduction”). Goldberg et al teach that the interchain disulfides of a mouse anti-biotin antibody were reduced to free thiols (page 276, under the heading “Reduction of Antibodies” and page 277, lines 1-7 under “Results and Discussion”) and the resulting reduced antibody was reacted with the bismaleimide, PDM, to form a product with over 90% cross-links (page 276, second column, under the heading “Cross-Linking with Bismaleimides” and page 276, first column, lines 4-9). Goldberg et al teach that the free SH groups are in spatial juxtaposition and are expected to react simultaneously with the PDM reagent (page 276, first column, lines 4-7).
Goldberg et al teach that the resulting cross-linked product was immobilized onto activated Sepharose as a solid support (page 276, second column, last full paragraph) and high levels of binding activity were observed (page 276, second column, lines 11-12). Goldberg et al demonstrate using an anti-biotin antibody cross linked with MPHPD that the leakage properties of the cross-linked immunoaffinity column were far superior to those of a column containing immobilized native antibody (page 279, second column, lines 7-10).
It would have been prima facie obvious prior to the effective filing date to utilize cross links in the goat polyclonal anti-immunoglobulin antibodies by reacting the reduced polyclonal antibodies with the PDM cross linker to form a product having 90% cross-links. One of skill in the art would have been motivated to do so because Goldberg et al teach that hydrolysis of the immobilized antibody light and/or heavy chains contaminate the affinity purified product. One of skill in the art would be motivated to minimize contamination of the product which was being quantified to increase the accuracy of the result.
18. Claim(s) 24-25 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 Foster (U.S. Patent #4,444,879), Raghuwanshi et al. (WO 2016/063299) and Goldenberg et al (Bioconjugate Chemistry, 1991, Vol. 2, pp. 275-289) as applied to claims 18-21 above, and further in view of Campbell et al. (Journal of Immunological Methods, 391, 2013, pages 1-13).
Please see Harding et al. in view of Bradwell et al. and further in view of Foster, Raghuwanshi et al. (WO 2016/063299) and Goldenberg et al (Bioconjugate Chemistry, 1991, Vol. 2, pp. 275-289) as set forth above.
Harding et al. in view of Bradwell et al. and further in view of Foster Raghuwanshi et al. (WO 2016/063299) and Goldenberg et al (Bioconjugate Chemistry, 1991, Vol. 2, pp. 275-289) fail to teach anti-free antibody immobilization on magnetic beads.
However, 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 immobilize the reagents exemplified by Harding et al. in view of Bradwell et al. and Foster in view of Raghuwanshi et al. (WO 2016/063299) and Goldenberg et al (Bioconjugate Chemistry, 1991, Vol. 2, pp. 275-289) on beads because 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 plates) and assayed, simultaneously, in a multi-plex format by Luminex® (mAb assay).
Response to Arguments
Applicant’s arguments are MOOT because the claim amendments have resulted in new grounds of rejections have been presented herein.
19. For reasons aforementioned, no claims are allowed.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LISA V COOK whose telephone number is (571)272-0816. The examiner works a flexible Part-Time schedule but can normally be reached on Monday, Thursday, and 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 on 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only.
For more information about the PAIR system, see http://portal.uspto.gov/external/portal. Should you have questions about access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
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.
Lisa V. Cook
Patent Examiner
Art Unit 1642
Hoteling
6/27/26
/LISA V COOK/Primary Examiner, Art Unit 1642
Prosecution Insights