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 .
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.
Priority
The present application claims benefit under 35 U.S.C. 119(e) to provisional application No. 63/357,801, filed 07/01/2022.
Information Disclosure Statement
The information disclosure statement (IDS) filed 02/01/2024 has been considered, initialed and is attached hereto.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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 1-20 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.
Claims 1 and 11 recite the claim language “at least one minute, preferably three minutes”, the claim language “preferably” is indefinite claim language because it raises question as to what is actually required of the claim. For example, it is not readily clear whether or not the preferable “three minutes” is required. See MPEP 2173.05(d), examples and preferences may lead to confusion over the intended scope of a claim.
Claim 1 recites at the preamble “an undiluted serum sample, or other body fluid or extract of cells or tissue from a subject”, however, the claim at step (ii) refers to only “an undiluted serum sample”. The claim is indefinite because the body of the claim is not consistent with the preamble regarding the sample of the claimed method.
Claims 6 and 15 recite “when the sample contains monoclonal immunoglobulins”, however, the claims are directed to detection of “free immunoglobulin light chains”. It is not readily clear if it was Applicant’s intention was to recite “contains monoclonal immunoglobulins” or “monoclonal immunoglobulin light chains”.
Claims 6 and 15 each recite “meets one or more additional criteria for the diagnosis of one or more disease or disorder associated with free immunoglobulin light chains”, however the claims fail to indicate what would or would not be encompassed and qualify as “additional criteria”. As such, the boundaries of the scope of the claim is unclear, as “additional criteria”, when given broadest reasonable interpretation, could encompass nearly any observable or measurable characteristic related to one’s health. It is not clear what additional criteria would and would not be diagnostic for a given disease (as notably the claim is not limited to a particular disease/condition, either).
Claim 20 recites “a kit suitable for carrying out a method according to claim 1”, the language “according to claim 1” is indefinite as this language fails to clearly suggest or imply any particular or specific components or reagents. It is not readily clear from this language what would necessarily be included (e.g., if this encompasses reagents for parts of the method of claim 1, or rather if this would encompass all the reagents necessary to perform the method of claim 1). Additionally, “a method of claim 1” is not the same as “the method of claim 1”, for example, “a method of claim 1”, as noted above, could merely be a part of the method, as in one method step of claim 1, or could encompass methods other methods similar in kind to claim 1 (referring to “a method according to claim 1”), as “as according” is generally interpreted as meaning as being in conformity with, or similar to.
Claim Rejections - 35 USC § 101
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.
Claims 6, 7 and 15-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and laws of nature/natural phenomena without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Claim 6 (and also claim 15) includes the limitations of claim 1 and 4 (and for claim, 15, include those of claim 11), and recites “analyzing and/or interpreting the immunofixation electrophoresis results and/or concluding about the health status of the subject”, when given broadest reasonable interpretation the claims encompass correlating presence or amount of free immunoglobulin light chain proteins or fragments thereof with a conclusion regarding the health status of the subject.
Claims 7-8 further limit claim 6 (and claims 16-17 similarly further limit claim 15), the claim reciting “wherein the disease or disorder associated with free-monoclonal light chains is selected from the group consisting of..” those recited at the claim. This limitation further narrows the disease/condition (subject’s status) as referred to above.
The natural relationship to which the claims are directed (i.e., the relation between free immunoglobulin light chain protein levels and a subject’s health status) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of free immunoglobulin light chain proteins in serum or urine (claims referring to claims depending from 1 and 11) and health status of a subject. The correlation is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility.
Additionally, the claims recite “and/or interpreting the immunofixation electrophoresis results”, which is broad claim language, and could, for example, encompass mental processes, namely concepts performed in the human mind including an observation, evaluation, judgement or opinion. As such, the indicated limitation is also considered to be an abstract idea.
Step 2A, Prong 2
The above-discussed limitations are insufficient to integrate into a practical application because those limitations are themselves the judicial exceptions and as such not a practical application thereof.
The claims also recite the assay steps of claims 1 and 4 (and claim 11 for claims 15-17), however none of those steps/elements recited at claims 1, 4 (or 11) further apply, rely on or use the judicial exception(s) in such a way that would amount to a practical application thereof. The steps referred to at the independent claims are steps that do not go beyond insignificant pre-solution activity, namely these steps are data gathering steps necessarily performed in order to obtain the data and use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Although the claims do recite “treatment” limitations (see “optionally, treating the subject for a disease when the sample contains monoclonal immunoglobulins and meets one or more additional criteria for the diagnosis of one or more disease or disorder associated with free monoclonal light chains”), this language is recited as an “optional” limitation, and is not specifically required when performing the method.
Additionally, it is noted that even if not recited as optional, the claim limitation is recited at an extremely high level of generality, and merely recites “treating the subject for a disease”. There is no particular or specific treatment recited in response to performing the assay. The limitation fails to have more than nominal or insignificant relationship to the exception(s) themselves, and amount to post-solution activity. The treatment limitation merely instructs one to “apply” the exception in a generic way, and as such is insufficient to amount to integration into a practical application.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Regarding the additional limitations/steps (i.e., those recited in addition to the above indicated judicial exceptions), the additionally recited steps/elements (recited at claims 1, 4 and further 11) fail to go beyond that which was well known, routine and conventional in the assay art. In particular, it was well known/routine to rely on the method of immunofixation electrophoresis to detect free immunoglobulin light chains in a patient sample. See for example, Singh et al. (Singh et al., Quantification by Ultrafiltration and Immunofixation Electrophoresis Testing for Monoclonal Serum Free Light Chains, Lab Medicine, 51, (2020), p. 592-600 (IDS entered 02/01/2024)), as evidenced by SPIFE Touch (SPIFE® Touch ImmunoFix Procedure, Helena Laboratories, https://www.helena.com/wp-content/uploads/2025/12/Pro220Rev5.pdf, (4 pages), Accessed: 06/17/2026) cited in more detail below. Singh et al. (2020) teach methods identifying the presence of serum free monoclonal light chains in serum samples, the method performing ultrafiltration SIFE using Helena equipment and supplies, determining serum levels of free light chains (SFLC) concentration (page 593, col. 2, para 3). Singh et al. teach performing SIFE using polyclonal antibodies for the relevant light chain, conducted with Helena reagents and equipment as per the manufacturer’s instructions (page 94, col. 1, para 1).
Further, see Wilhite et al., Multiple Myeloma: Detection of free monoclonal light chains by modified immunofixation electrophoresis with antisera against free light chains, Practical Laboratory Medicine, 27, (2021) (8 pages) (IDS entered 02/01/2024, Wilhite (cited in detail below) also teach a modified SIFE (immunofixation electrophoresis protocol, see at page 3), the method comprising depositing a portion of undiluted serum to the SIFE gels (step 1), electrophoresing the plate to provide protein separation profile (step 2), contacting the electrophoresed gel with a solution comprising at least one capture antibody (applied antisera, see step 3), the capture antibody specific for free immunoglobulin light chain proteins or fragments (see step 3, to free kappa or lambda light chains, the contacting under conditions that permit formation of immunocomplexes). Wilhite further teach removing unbound capture antibody by blotting with blotting paper (see step 4), contacting the gel with wash solution incubated for 3 minutes, removing the wash solution by blotting (this process repeated 2 more times, thereby also addressing present claim 1, step vi). Also noted, Wilhite further perform a staining step for the immunocomplexes formed (see Wilhite page 3, step 8).
Applicant’s originally filed specification also acknowledges immunofixation electrophoresis as a known method, recognized and used in the prior art for free immunoglobulin light chain, the background at the specification suggesting the claimed method is an improved technique. However, as presently claimed, the method recited does not appear to go beyond that which was well known in the art at the time (referring to the cited art referenced above).
There is no evidence of record to indicate the additional elements/steps (recited in addition to the judicial exceptions themselves), alone or in combination, go beyond that which was well-understood, routine and conventional activity regarding the detection of free immunoglobulin light chains.
Claim Rejections - 35 USC § 102
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, 5-10 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wilhite et al., Multiple Myeloma: Detection of free monoclonal light chains by modified immunofixation electrophoresis with antisera against free light chains, Practical Laboratory Medicine, 27, (2021) (8 pages) (IDS entered 02/01/2024) as evidenced by as evidenced by SPIFE® Touch ImmunoFix Procedure, Helena Laboratories, https://www.helena.com/wp-content/uploads/2025/12/Pro220Rev5.pdf, (4 pages), Accessed: 06/17/2026.
Wilhite et al. is cited as prior art, as the present application names fewer joint inventors than the cited publication. See MPEP 2153.01(a),
Wilhite et al. teach a modified SIFE (immunofixation electrophoresis protocol, see at page 3), the method comprising depositing a portion of undiluted serum to the SIFE gels (step 1), electrophoresing the plate to provide protein separation profile (step 2), contacting the electrophoresed gel with a solution comprising at least one capture antibody (applied antisera, see step 3), the capture antibody specific for free immunoglobulin light chain proteins or fragments (see step 3, to free kappa or lambda light chains, the contacting under conditions that permit formation of immunocomplexes). Wilhite further teach removing unbound capture antibody by blotting with blotting paper (see step 4), contacting the gel with wash solution incubated for 3 minutes, removing the wash solution by blotting (this process repeated 2 more times, thereby also addressing present claim 1, step vi). Also noted, Wilhite further perform a staining step for the immunocomplexes formed (see Wilhite page 3, step 8).
Wilhite is teaching Helena Touch equipment and reagents (see referring to methods at page 3). However, fails to specify where or not the gel plate has an anodic side and cathodic side, as recited at (i). However, see cited as evidence SPIFE® Touch, it is understood from the citation of SPIFE® that the methods comprise gel plates (Helena Touch) have an anodic and cathodic side, separation based on migration of positively charged proteins toward cathodic side (see e.g., page 4, referring to migration in the cathodic region).
Regarding claim 2, Wilhite teach limit of detection to be “about 1.78mg/L”, which is “about” this concentration is considered to encompass, 1.75 mg/L (as 1.75 mg/L is substantially close and the language “about” suggests those concentrations that are near to 1.78.
Regarding claim 3, see also Wilhite at page 3, method step 4.
Regarding claim 5, see Wilhite teach human subject samples (see page 3, first paragraph).
Regarding claim 6, See Wilhite teach the method for screening for monoclonal gammopathies (abstract), as such, given broadest reasonable interpretation, addresses analyzing results, concluding about one’s health status.
Regarding claims 7 and 8, see Wilhite teaching MM, more specifically, LCMM (page 2, paragraphs 1-2).
Regarding claim 9 and 10, Wilhite teach, neoplastic gammopathies that predominantly or exclusively produce free light chains can be hard to detect, especially when looking for minimal residual disease in the posttreatment setting. Wilhite does teach detection in those having been treated for NMG (see MM treated via autologous stem cell transplantation, caption at figure 1).
Regarding claim 20, Wilhite teach their methods conducted using available kits, specifically see e.g., page 3, para 2 (quantification of SFLC conducted by suing kits procured from The Binding Site and assayed with Optilite analyzer), further see step 4, “HELENA SIFE kits”, antiserum was blotted with SIFE filters in Helena SIFE kits). As such, Wilhite anticipates claim 20, as they are teaching a kit for carrying out methods according to claim 1, the kits comprising at least some components recited at claim 20, for example, at least blotting paper.
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.
Claim(s) 1-3 and 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al., Quantification by Ultrafiltration and Immunofixation Electrophoresis Testing for Monoclonal Serum Free Light Chains, Lab Medicine, 51, (2020), p. 592-600 (IDS entered 02/01/2024) in view of Warren et al., US Patent No. 5,200,045, as evidenced by SPIFE®® Touch ImmunoFix Procedure, Helena Laboratories, https://www.helena.com/wp-content/uploads/2025/12/Pro220Rev5.pdf, (4 pages), Accessed: 06/17/2026.
Singh et al. (2020) teach methods identifying the presence of serum free monoclonal light chains in serum samples, the method performing ultrafiltration SIFE using Helena equipment and supplies, determining serum levels of free light chains (SFLC) concentration (page 593, col. 2, para 3). Singh et al. teach performing SIFE using polyclonal antibodies for the relevant light chain, conducted with Helena reagents and equipment as per the manufacturer’s instructions (page 94, col. 1, para 1).
See as evidenced by SPIFE® Touch ImmunoFix Procedure, the method performed according to Helena protocols (taught by Singh) comprises depositing sample on a deposit area of the an electrophoretic gel plate having an anodic side and cathodic side, allows electrophoretic migration of negatively charged/acidic proteins within deposited samples to migrate toward cathodic end of gel plate, electrophoresing (see page 3, IV, A-C), contacting electrophoresed gel with solution comprising at least one capture antibody (see protocol for immunofixation, V, steps 1-7, see contacting is performed under conditions that permit formation of precipitate and/or formation of detectable immunocomplexes within the separation profile), removing unbound capture antibody (see V, described at steps 9-13, blotting with blotting paper, referring to as blotter C or blotter D). See further SPIFE® Touch indicates a wash step (using saline or Clear wash, both which read on “wash solution” as claimed), and further staining (see steps 1-5, thereby also addressed the claimed optional staining step).
Singh et al. is teaching serum samples that are undiluted, see page 594, col. 1, para 1, performed according to manufacturer’s instructions, without diluting the concentrated filtrate.
Singh et al. fails to teach how long the wash step takes to complete, and as such fails to teach washing for at least 1 minute (as recited at step (v) of claim 1).
Warren et al. (Assignee Helena Laboratories) teach a method and apparatus for removing unreacted protein and unreacted antisera from a gel plate during immunofixation electrophoresis (abstract), specifically their method and apparatus requiring a washing/pressing cycle of about 10 minutes (col. 1, lines 61-65). See specifically, col. 4, lines 24-37, a quick immersion in saline, a first press cycle of about 5 minutes, and a four minute wash cycle, followed by a second press cycle of about 1 minute. Even further Warren referring to conventional methods (previous to Warren’s technique), Warren acknowledge conventional technique also involves washing for 10 minutes (thereby also addressing at least 1 minute).
Although SPIFE® Touch (and as such, also Singh) is silent as to the duration for the wash step, it would have been obvious that the gel be in contact with the wash solution for 4 or 10 minutes (thereby addressing a duration of at least one minute) prior to removing the wash solution because the prior art recognized systems like that used in Singh (like thee SPIFE® Touch system), under improved conditions, to achieve wash comprising wash steps including a contact times described as “quick” and as “four minute wash cycle” (see referring to Warren et al., which is also a Helena Laboratories system, Warren is teaching their system as improved achieving a total washing/pressing cycle (cycle which includes wash solution contact steps) in just 10 minutes total, or further in 40 minutes using conventional methods (which also addresses at least 1 minute). Although SPIFE® Touch fails to indicate the contact time in which the gel and wash solution are in contact, it would be obvious to use durations as taught by Warren as an obvious matter of applying a known technique to known methods, one motivated because Warren et al. is in reference to analogous technique (i.e., is also immunofixation electrophoresis), Warren demonstrating their duration as suitable for removing the unreacted antisera from the gel. Further, one having ordinary skill would have a reasonable expectation of success because like SPIFE® Touch, Warren et al. is also relevant to immunofixation electrophoresis, and because it is similarly in reference to Helena Laboratories system and the same type of assay.
Regarding claim 2, Singh teach more than 1.75 mg/L of sample (see for example see cases at pages 597-599, e.g., case 1, calculated to be 82.98 mg/L, case 2, 65.0 mg/L, case 3, 178.01 mg/L, etc.).
Regarding claim 3, Singh et al. and the cited prior art teach a method substantially as claimed, however fails to teach the details of the wash step, and as such fails to teach the series of steps recited at claim 3, wherein the incubation in wash solution is for 3 minutes, further repeating the steps twice or more (claim 3).
However, see as cited previously above, Warren acknowledge both conventional and their faster wash techniques, Warren describe immersing in saline, and then higher pressure to shorten the duration for when performing conventional. Regarding conventional technique, Warren describe the process comprising after contact with saline, incubate with wash solution for 10 minutes, repeating the steps (col. 1, lines 44-58), Warren teach optimizing conditions by changing applied pressure such to shorten cycle by immersing in saline, pressing for about 5 minutes, a four minute wash cycle and second press cycle of about 1 minute, thereby reducing wash times.
Based on the prior art, duration of contact with wash solution, and repeating the steps is a result effective variable, namely a variable optimized in order to achieve wash/removal of unreacted proteins (Warren), Warren demonstrate this is a variable that is optimizable through routine experimentation, for example Warren demonstrate adjusting pressure applied as an experimental condition that can be changed to impact the length of the incubation with solution for wash (shorter or longer times, see Warren’s technique versus conventional wash as recognized by Warren), which effects removal of unreacted proteins. Warren teach reducing contact time to as little as 4 minutes, which is substantially similar to the claimed 3 minutes. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), see MPEP 2144.05.
It would have been prima facie obvious to one having ordinary skill in the art to have arrived the series of wash steps as recited at claim 3, comprising a duration of 3 minutes for contact with the wash solution, out of routine optimization of experimental conditions (the prior art teaching for example 10, or as little as 4, minutes), in order to achieve removal of unreacted proteins from the gel. In the present case, the prior art as set forth above, demonstrate the general conditions, regarding the wash steps of the assay, were known and performed by those of ordinary skill in the art. One would have been motivated to optimize conditions in order to uncover the optimum duration necessary in order to remove unreacted reagent. Further, given the similarity between 3 and 4 minutes, one having ordinary skill would not expect a critical difference (would have a reasonable expectation of success) in the results achieved in terms of the removal of unreacted reagent.
Regarding claim 5, Singh et al. is teaching human serum specimens (see from those with known light chain myelomas and controls).
Regarding claim 6, Singh et al. is suggesting their method as a way to monitor the course of disease, and as such, addresses analyzing and/or interpreting the results and/or concluding about the health of a subject (abstract, page 593, col. 2, last para, detected in myelomas with active disease, see also page 595, end of col. 2). In correlating the results with active disease as cited presently, when given broadest reasonable interpretation, Singh et al. is “analyzing and/or interpreting the immunofixation electrophoresis results and/or concluding about the health status of the subject”.
Regarding claims 7 and 8, Singh is teaching subjects with multiple/plasma cell myeloma (MM), see at page 593, col. 2, para 4), namely light chain myeloma (LCMM) (see page 593, col. 2, para 2).
Claim(s) 4 is rejected under 35 U.S.C. 103 as being unpatentable over Singh et al., in view of Warren et al., as evidenced by SPIFE® Touch, as applied to claim 1 above, and further in view of Kuriakose et al., A Study of Free Light Chain Assay and Serum Immunofixation Electrophoresis for the Diagnosis of Monoclonal Gammopathies, Ind. J. Clin. Biochem., 34(1), (2019), p. 76-81.
Regarding claim 4, Singh et al. and the cited art teach a method substantially as claimed, however fails to teach wherein at least one aliquot portion of the undiluted sample is deposited on the gel plate as a reference which is not submitted to step (iii), but is instead contacted with a fixative solution rather than capture antibodies (claim 4).
See further Kuriakose et al. who also teach detection of free light chain using immunofixation electrophoresis (e.g., abstract), Kuriakose teach one lane treated with fixative solution to fix all proteins to provide a reference pattern, the other lanes treated with antisera.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified Singh et al. and the cited art in order to deposit one aliquot of the sample (undiluted sample of Singh et al.) in the plate as a reference, contacted with fixative rather than antisera, as an obvious matter of applying a known technique to a known method, i.e., a known technique for providing reference/control data for comparison, as in Kuriakose, in order to reach conclusion regarding detection. One having ordinary skill in the art would have had a reasonable expectation of success because like Singh et al., Kuriakose teach immunofixation electrophoresis (both are directed to the same type of assay technique, and as such one would expect success applying a reference as in Kuriakose).
Claim(s) 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al. in view of Warren et al., as evidenced by SPIFE® Touch, as applied to claim 5 above, and further in view of Lee et al., Serum Free Light Chain in Neoplastic Monoclonal Gammopathies: Relative Under-Detection of Lambda Dominant Kappa/Lambda Ratio, and Underproduction of Free Lambda Light Chains, as Compared to Kappa Light Chains, in Patients with Neoplastic Monoclonal Gammopathies, J. Clin. Med. Res, 10(7), (2018), p. 562-569 (IDS entered 02/01/2024).
Regarding claim 9, the combination of the cited art teach a method substantially as claimed, however fails to teach sample from subject previously treated for disease or disorder associated with free monoclonal light chains selected from the group recited at claim 9.
Regarding claim 10, the combination of the cited art teach a method substantially as claimed, however fails to teach the subject has received or is receiving treatment for a Neoplastic monoclonal gammopathy (NMG).
It is known in the prior art that quantitative evaluation of serum free light chains is recommended for the work up of monoclonal gammopathies (see Lee et al., at the abstract). Lee et al. suggest the use of immunofixation electrophoresis technique for use in treatment follow up (i.e., performing the assay to measure in those receiving treatment for NMG). As such, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed to have modified Singh et al. and the cited prior art, perform the method on to detect light chains in subjects undergoing treatment for NMG, as an obvious matter to try for the purpose of following up a subject’s treatment (treatment follow-up, i.e. monitoring), one motivated to try because Lee specifically suggest immunofixation electrophoresis as usable for this purpose. One having ordinary skill in the art would have a reasonable expectation of success because Lee specifically suggest this assay technique appliable for assay in those receiving such treatments.
Claim(s) 11-13 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Sing et al. in view of Warren et al. and Levinson et al., Urine Protein Electrophoresis and Immunofixation Electrophoresis Supplement One Another in Characterizing Proteinuria, Annals of Clinical & Laboratory Science, 30(1), (2000), p.79-84, and as evidenced by SPIFE® Touch.
Singh et al. in view of Warren et al., and as evidenced by SIFE Touch teaches a method as substantially as claimed (see Singh et al. modified by Warren et al., and as evidenced by SIFE TOUCH, as discussed above under the rejection of claim 1, it would have been prima facie obvious to one having ordinary skill in the art to have modified Singh et al. for the reasons as indicated above, as the same reasoning also applies presently).
Regarding claim 11, Singh et al.’s method is directed toward demonstrating the utility of ultrafiltration SIFE to detect free light chains in serum (see as cited above, and abstract), however Singh does also acknowledge urine examination as the preferred method for diagnosis of light chain plasma cell myelomas (i.e., it is understood from Singh et al. that light chains are detectable in either samples, blood or urine, urine considered preferred at the time of Singh, Singh also further showing serum as suitable when performing ultracentrifugation immunofixation electrophoresis). See also page 593, col. 1, first full paragraph, Singh teach light chain myelomas constitute 13-15% of all plasma cell myelomas and require identification of monoclonal light chains in urine or serum. See specifically, page 593, col. 2, Singh et al. does also include urine specimens concentrated and examined using electrophoresis and immunofixation. Singh acknowledge at page 596, col. 2, para 2, that urine examination is better for detecting monoclonal light chains in LCMM.
However, although Singh et al. does teach concentrating urine samples to provide a concentrated sample (e.g., page 593, col. 2, para 3 concentrated using Mincon B15 filters), Singh fails to specify by what volume, and as such fails to teach from about 5 fold to about 200 fold, inclusive, as recited at claim 11.
Levinson also teach detection of protein in urine samples using immunofixation electrophoresis, Levinson teach, prior to electrophoresis, urine samples are mechanically concentrated (similarly as in Singh et. al., using Mincon B15) about 100X (100 fold), then performed IFE (see page 80, col. 1, para 1).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified Singh et al. and the cited art, when performing ultracentrifugation SPIFE®, as in Singh, such that when concentrating urine samples as Singh, that urine samples be concentrated by 100 fold as in Levinson, as an obvious matter of applying a known technique to a known method. In particular, Singh et al. already teach the base method, Singh notably also using Mincon B15 as cited in Levinson for the purpose of concentrating sample prior to immunofixation electrophoresis. Levinson is similarly performing methods to detect targeted protein in a urine sample, Levinson teaching 100 fold as an appropriate parameter for concentrating sample. As such, one having ordinary skill would have found it obvious to have applied the technique of Levinson, and the results would have been predictable, specifically the sample would be expected sufficiently concentrated for detection.
Regarding claim 12, Singh et al. and the cited prior art teach a method substantially as claimed, however fails to teach the details of the wash step, and as such fails to teach the series of steps recited at claim 12, wherein the incubation in wash solution is for 3 minutes, further repeating the steps twice or more (claim 12).
However, see as cited previously above, Warren acknowledge both conventional and their faster wash techniques, Warren describe immersing in saline, and then higher pressure to shorten the duration for when performing conventional. Regarding conventional technique, Warren describe the process comprising after contact with saline, incubate with wash solution for 10 minutes, repeating the steps (col. 1, lines 44-58), Warren teach optimizing conditions by changing applied pressure such to shorten cycle by immersing in saline, pressing for about 5 minutes, a four minute wash cycle and second press cycle of about 1 minute, thereby reducing wash times.
Based on the prior art, duration of contact with wash solution, and repeating the steps is a result effective variable, namely a variable optimized in order to achieve wash/removal of unreacted proteins (Warren), Warren demonstrate this is a variable that is optimizable through routine experimentation, for example Warren demonstrate adjusting pressure applied as an experimental condition that can be changed to impact the length of the incubation with solution for wash (shorter or longer times, see Warren’s technique versus conventional wash as recognized by Warren), which effects removal of unreacted proteins. Warren teach reducing contact time to as little as 4 minutes, which is substantially similar to the claimed 3 minutes. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), see MPEP 2144.05.
It would have been prima facie obvious to one having ordinary skill in the art to have arrived the series of wash steps as recited at claim 12, comprising a duration of 3 minutes for contact with the wash solution, out of routine optimization of experimental conditions (the prior art teaching for example 10, or as little as 4, minutes), in order to achieve removal of unreacted proteins from the gel. In the present case, the prior art as set forth above, demonstrate the general conditions, regarding the wash steps of the assay, were known and performed by those of ordinary skill in the art. One would have been motivated to optimize conditions in order to uncover the optimum duration necessary in order to remove unreacted reagent. Further, given the similarity between 3 and 4 minutes, one having ordinary skill would not expect a critical difference (would have a reasonable expectation of success) in the results achieved in terms of the removal of unreacted reagent.
Regarding claim 13, see as evidenced by SPIFE® Touch, the methods of Singh include staining comprising drying the gel and staining with dye suitable for quantitation and visual examination (see between V and VI, particularly V at step 13, dried, and the gel subsequently stained for visualization).
Regarding claim 15, Singh et al. is suggesting their method as a way to monitor the course of disease, and as such, addresses analyzing and/or interpreting the results and/or concluding about the health of a subject (abstract, page 593, col. 2, last para, detected in myelomas with active disease, see also page 595, end of col. 2). In correlating the results with active disease as cited presently, when given broadest reasonable interpretation, Singh et al. is “analyzing and/or interpreting the immunofixation electrophoresis results and/or concluding about the health status of the subject”.
Regarding claims 16-17, Singh is teaching subjects with multiple/plasma cell myeloma (MM), see at page 593, col. 2, para 4), namely light chain myeloma (LCMM) (see page 593, col. 2, para 2).
Claim(s) 14 is rejected under 35 U.S.C. 103 as being unpatentable over Singh et al., in view of Warren et al. and Levinson et al., as evidenced by SPIFE® Touch, as applied to claim 11 above, and further in view of Kuriakose et al., A Study of Free Light Chain Assay and Serum Immunofixation Electrophoresis for the Diagnosis of Monoclonal Gammopathies, Ind. J. Clin. Biochem., 34(1), (2019), p. 76-81.
Regarding claim 14, Singh et al. and the cited art teach a method substantially as claimed, however fails to teach wherein at least one aliquot portion of the undiluted sample is deposited on the gel plate as a reference which is not submitted to step (iii), but is instead contacted with a fixative solution rather than capture antibodies (claim 4).
See further Kuriakose et al. who also teach detection of free light chain using immunofixation electrophoresis (e.g., abstract), Kuriakose teach one lane treated with fixative solution to fix all proteins to provide a reference pattern, the other lanes treated with antisera.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified Singh et al. and the cited art in order to deposit one aliquot of the sample (undiluted sample of Singh et al.) in the plate as a reference, contacted with fixative rather than antisera, as an obvious matter of applying a known technique to a known method, i.e., a known technique for providing reference/control data for comparison, as in Kuriakose, in order to reach conclusion regarding detection. One having ordinary skill in the art would have had a reasonable expectation of success because like Singh et al., Kuriakose teach immunofixation electrophoresis (both are directed to the same type of technique, and as such one would expect success applying a reference as in Kuriakose).
Claim(s) 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Singh et al. in view of Warren et al. and Levinson et al., as evidenced by SPIFE® Touch, as applied to claim 11 above, and further in view of Lee et al., Serum Free Light Chain in Neoplastic Monoclonal Gammopathies: Relative Under-Detection of Lambda Dominant Kappa/Lambda Ratio, and Underproduction of Free Lambda Light Chains, as Compared to Kappa Light Chains, in Patients with Neoplastic Monoclonal Gammopathies, J. Clin. Med. Res, 10(7), (2018), p. 562-569 (IDS entered 02/01/2024).
Regarding claim 18, the combination of the cited art teach a method substantially as claimed, however fails to teach sample from subject previously treated for disease or disorder associated with free monoclonal light chains selected from the group recited at claim 9.
Regarding claim 19, the combination of the cited art teach a method substantially as claimed, however fails to teach the subject has received or is receiving treatment for a Neoplastic monoclonal gammopathy (NMG).
It is known in the prior art that quantitative evaluation of serum free light chains is recommended for the work up of monoclonal gammopathies (see Lee et al., at the abstract). Lee et al. suggest the use of immunofixation electrophoresis technique for use in treatment follow up (i.e., performing the assay to measure in those receiving treatment for NMG).
As such, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed to have modified Singh et al. and the cited prior art, perform the method on to detect light chains in subjects undergoing treatment for NMG, as an obvious matter to try for the purpose of following up a subject’s treatment (treatment follow-up, i.e. monitoring), one motivated to try because Lee specifically suggest immunofixation electrophoresis as usable for this purpose. One having ordinary skill in the art would have a reasonable expectation of success because Lee specifically suggest this assay technique appliable for assay in those receiving such treatments.
Claim(s) 20 is rejected under 35 U.S.C. 103 as being unpatentable over Golias, US Patent No. 5,185,066 in view of Preuss et al., WO2010/085345 A1.
Golias teach a kit for immunofixation electrophoresis of a sample, the kit comprising at least one antiserum, at least one control serum (see claim 24 of Golias). See further the invention of Golias include antiserum to human lambda light chain (e.g., claim 18).
Claim 20 recites instructions according to claim 1 and further “one or more of” those components listed, and as noted above, Golias teach antiserum to lamda light chain (i.e., capture antibody for free light chain).
Golias fails to recite “instructions”. See MPEP 2111.05, I., B. Where a product merely serves as a support for printed matter, no functional relationship exists. Additionally, where the printed matter and product do not depend upon each other, no functional relationship exists. For example, in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals. In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864.
However, see for example, Preuss, Preuss teach providing diagnostic reagent kits, teaching kit including instructions or other printed material on how to use the various components of the kits for diagnostic purposes (page 31, lines 29-30).
Regarding the present recited claim language, the claim only requires that the kit comprise one of the claimed components from those listed at claim 20, further the language “a kit suitable for carrying out a method of according to claim 1” is directed toward the intended use of the claimed product, and further rand “instructions according to the method of claim 1”, when given broadest reasonable interpretation, merely encompasses instructions to use the claimed reagents in a method such as that of claim 1, which, relative to the component that is capture antibody, merely requires contacting electrophoresed gel with a solution comprising the capture antibody.
Although the instructions as claimed amount to printed matter, and there is no functional relationship between the instructions and the kit components (the instructions are not functionally related with the associated components of the kit), it is also the case regarding assay kits/kits comprising components for performing assay methods, that it would have been obvious to have included as part of the kit, instruction regarding how to use the claimed kit components, as in Preuss, as an obvious matter of a applying a known technique to a known product. Specifically, as shown by Preuss, it was known to include instruction, one motivated in order to instruct how the reagent/components are to be used. Considering that Golias is also teaching antiserum for the purpose of immunofixation capture of target such as light chains that have been electrophoresed on a gel, it would have been obvious that included instructions for using antiserum would be instructions that achieve such a step “according to claim 1”, and as such, the combination of the cited art also addresses the claim.
One having ordinary skill would have a reasonable expectation incorporating in the kit, instruction, since it was known to include instructions with assay/reagent kits (as is demonstrated by Preuss).
Claim(s) 4 is rejected under 35 U.S.C. 103 as being unpatentable over Wilhite et al. in view of Kuriakose et al., A Study of Free Light Chain Assay and Serum Immunofixation Electrophoresis for the Diagnosis of Monoclonal Gammopathies, Ind. J. Clin. Biochem., 34(1), (2019), p. 76-81 (IDS entered 02/01/2024), as evidenced by SPIFE® Touch.
Wilhite teach a method substantially as claimed (see as cited in detail above), however fails to teach wherein an aliquot portion of the undiluted sample is deposited on the gel plate as a reference which is not submitted to the step recited as (iii) presently, but is instead contacted with a fixative solution rather than with capture antibodies (claim 4).
See Kuriakose et al. who also teach detection of free light chain using immunofixation electrophoresis (e.g., abstract), Kuriakose teach one lane treated with fixative solution to fix all proteins to provide a reference pattern, the other lanes treated with antisera.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified Wilhite et al. and the cited art in order to deposit one aliquot of the sample (undiluted sample of Wilhite et al.) in the plate as a reference, contacted with fixative rather than antisera, as an obvious matter of applying a known technique to a known method, i.e., a known technique for providing reference/control data for comparison, as in Kuriakose, in order to reach conclusion regarding detection. One having ordinary skill in the art would have had a reasonable expectation of success because like Wilhite et al., Kuriakose teach immunofixation electrophoresis (both are directed to the same type of assay technique, and as such one would expect success applying a reference as in Kuriakose).
Claim(s) 11-13 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Wilhite et al. in view of Singh et al. and Levinson et al., as evidenced by SPIFE® Touch.
Regarding claim 11, claim 11 is substantially similar to claim 1, however claim 11 recites identifying in a sample that is a urine sample, and recites a step of concentration a urine sample to reduce the volume from about 5 fold to about 200 fold.
As cited previously above, Wilhite teach a method substantially as claimed (see as cited previously above, same series of method steps).
However, Wilhite differs from claim 11 in that Wilhite fails to teach identifying in a sample that is a urine sample, and recites a step of concentration a urine sample to reduce the volume from about 5 fold to about 200 fold.
Singh et al.’s method (as cited in detail previously above) is directed toward demonstrating the utility of ultrafiltration SIFE to detect free light chains in serum (see as cited above, and abstract), however Singh does also acknowledge urine examination as the preferred method for diagnosis of light chain plasma cell myelomas (i.e., it is understood from Singh et al. that light chains are detectable in either samples, blood or urine, urine considered preferred at the time of Singh, Singh also further showing serum as suitable when performing ultracentrifugation immunofixation electrophoresis). See also page 593, col. 1, first full paragraph, Singh teach light chain myelomas constitute 13-15% of all plasma cell myelomas and require identification of monoclonal light chains in urine or serum. See specifically, page 593, col. 2, Singh et al. does also include urine specimens concentrated and examined using electrophoresis and immunofixation. Singh acknowledge at page 596, col. 2, para 2, that urine examination is better for detecting monoclonal light chains in LCMM.
However, although Singh et al. does teach concentrating urine samples to provide a concentrated sample (e.g., page 593, col. 2, para 3 concentrated using Mincon B15 filters), Singh fails to specify by what volume, and as such fails to teach from about 5 fold to about 200 fold, inclusive, as recited at claim 11.
Levinson also teach detection of protein (monoclonal free light chains, i.e., Bence-Jones proteins) in urine samples using immunofixation electrophoresis, Levinson teach, prior to electrophoresis, urine samples are mechanically concentrated (similarly as in Singh et. al., using Mincon B15) about 100X (100 fold), then performed IFE (see page 80, col. 1, para 1).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified Wilhite et al. and the cited art, to detect in samples that are concentrated urine samples (as in Singh et al.), as a simple substitution of one art recognized sample having detectable light chains for another, see as cited above, both were art recognized samples known suitable for detecting/quantitating free light chains (see Singh et al., Levinson et at). Further, the modification would have been considered an obvious matter to try, namely trying urine in place of serum, one similarly motivated because both were recognized suitable for this purpose in the prior art (Singh and Levinson). One having ordinary skill in the art would have a reasonable expectation of success because the prior art already demonstrated detection in samples that are urine (referring to above).
Further, one detecting in concentrated urine, it would have been obvious to have concentrated by 100 fold as in Levinson, as an obvious matter of applying a known technique to a known method. In particular, Singh et al. already teach the base method, Singh notably also using Mincon B15 as cited in Levinson for the purpose of concentrating sample prior to immunofixation electrophoresis. Levinson is similarly performing methods to detect targeted protein in a urine sample, Levinson teaching 100 fold as an appropriate parameter for concentrating sample. As such, one having ordinary skill would have found it obvious to have applied the technique of Levinson, and the results would have been predictable, specifically the sample would be expected sufficiently concentrated for detection.
Regarding claim 12, see also Wilhite at page 3, method step 4.
Regarding claim 13, see also Wilhite at page 3, method steps 8 and 9.
Regarding claim 15, see Wilhite teach the method for screening for monoclonal gammopathies (abstract), as such, given broadest reasonable interpretation, addresses analyzing results, concluding about one’s health status.
Regarding claims 16 and 17, see Wilhite teaching MM, more specifically, LCMM (page 2, paragraphs 1-2).
Claim(s) 14 is rejected under 35 U.S.C. 103 as being unpatentable over Wilhite et al. in view of Kuriakose et al., A Study of Free Light Chain Assay and Serum Immunofixation Electrophoresis for the Diagnosis of Monoclonal Gammopathies, Ind. J. Clin. Biochem., 34(1), (2019), p. 76-81, as evidenced by SPIFE® Touch.
Wilhite (as evidenced by SPIFE® Touch) teach a method substantially as claimed (see as cited in detail above), however fails to teach wherein an aliquot portion of the undiluted sample is deposited on the gel plate as a reference which is not submitted to the step recited as (iii) presently, but is instead contacted with a fixative solution rather than with capture antibodies (claim 14).
See Kuriakose et al. who also teach detection of free light chain using immunofixation electrophoresis (e.g., abstract), Kuriakose teach one lane treated with fixative solution to fix all proteins to provide a reference pattern, the other lanes treated with antisera.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified Wilhite et al. and the cited art in order to deposit one aliquot of the sample (undiluted sample of Wilhite et al.) in the plate as a reference, contacted with fixative rather than antisera, as an obvious matter of applying a known technique to a known method, i.e., a known technique for providing reference/control data for comparison, as in Kuriakose, in order to reach conclusion regarding detection. One having ordinary skill in the art would have had a reasonable expectation of success because like Wilhite et al., Kuriakose teach immunofixation electrophoresis (both are directed to the same type of assay technique, and as such one would expect success applying a reference as in Kuriakose).
Claim(s) 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Wilhite et al. in view of Singh et al. and Levinson et al., as evidenced by SPIFE® Touch, as applied to claim 11 above, and further in view of Lee et al., Serum Free Light Chain in Neoplastic Monoclonal Gammopathies: Relative Under-Detection of Lambda Dominant Kappa/Lambda Ratio, and Underproduction of Free Lambda Light Chains, as Compared to Kappa Light Chains, in Patients with Neoplastic Monoclonal Gammopathies, J. Clin. Med. Res, 10(7), (2018), p. 562-569 (IDS entered 02/01/2024).
Regarding claim 18, the combination of the cited art teach a method substantially as claimed, however fails to teach sample from subject previously treated for disease or disorder associated with free monoclonal light chains selected from the group recited at claim 9.
Regarding claim 19, the combination of the cited art teach a method substantially as claimed, however fails to teach the subject has received or is receiving treatment for a Neoplastic monoclonal gammopathy (NMG).
It is known in the prior art that quantitative evaluation of serum free light chains is recommended for the work up of monoclonal gammopathies (see Lee et al., at the abstract). Lee et al. suggest the use of immunofixation electrophoresis technique for use in treatment follow up (i.e., performing the assay to measure in those receiving treatment for NMG). As such, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed to have modified Singh et al. and the cited prior art, perform the method on to detect light chains in subjects undergoing treatment for NMG, as an obvious matter to try for the purpose of following up a subject’s treatment (treatment follow-up, i.e. monitoring), one motivated to try because Lee specifically suggest immunofixation electrophoresis as usable for this purpose. One having ordinary skill in the art would have a reasonable expectation of success because Lee specifically suggest this assay technique appliable for assay in those receiving such treatments.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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