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
It is acknowledged, Applicant claims benefit under 35 U.S.C. 119(e) to provisional application No. 63/294,083, filed 12/28/2021.
Status of the Claims
Claims 1-30 are pending; claims 4, 6, 10, 12, 13, 25, 26 and 28 are amended; claims 1-30 are examined below.
Withdrawn Objections/Rejections
The previous rejection of claims 4 and 6 under 35 U.S.C. 112(b) is withdrawn in response to Applicant’s amendments to the claims.
The previous rejection of claim 6 under 35 U.S.C. 101 is withdrawn in response to Applicant’s amendments to the claims which now clearly indicate “passing or failing” is tantamount with determining presence of target. However, see the rejection of claim 4 is maintained as claim 4, passing or failing encompasses comparing to a pre-determined concentration (the comparing step is considered to be an abstract idea).
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.
Claim 4 is rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea 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 4 recites “the method further comprises passing or failing the micronized tissue sample based at least in part on the determined concentration…, wherein passing or failing the micronized tissue sample includes comparing the determined concentration of the target antigen to a pre-determined threshold concentration level” (concentration, claim 4, ). Specifically, see as set forth in the MPEP, Groupings of Abstract Ideas, the claimed limitation is considered a mental process/concept performed in the human mind. The claims under their broadest reasonable interpretation, cover determining a passing or failing within the human mind, namely by comparing information regarding sample to control or target data (comparing to a threshold value), which represents abstract ideas.
Similar concepts involving comparing information regarding a sample or test subject to a control or target data have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo (which also involved specific numerical cutoff levels).
Step 2A, Prong 2
Regarding step 2A, prong 2, in addition to the limitation directed to the judicial exception as indicated above, see also the steps/elements recited at claim 1. The additionally recited steps involve the immobilizing, the adding and the detecting as claimed at claim 1 do not further apply, rely on or use the judicial exception in a way that imposes a meaningful limit on the judicial exception. Rather the steps recited at claim 1 (recited in addition to the judicial exception) amount to data gathering activity, which is a form of insignificant extra-solution activity. These are steps necessarily informed to obtain the data.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements further do not add significantly more to the judicial exception. The additionally recited claim elements fail to amount to more than that which well-known, routine and conventional in the assay art. As indicated in detail previously above, the steps/elements of claim are also considered data gathering steps, namely insignificant extra-solution activity, and are not steps/elements performed in an unconventional way such to provide an “inventive concept”.
For example, ELISA was a well-known, art recognized technique known in the art for detecting laminin in samples (see for example, Castillo WO98/15179 , teach (see page 63, lines 4 to page 64, line 24; page 65, lines 4-8; see also Castillo claim 29) for detection and quantitation of laminin, various types of ELISA can be used, Castillo specifically teaching two-site or sandwich type ELISA as preferred. Regarding this type of ELISA, Castillo teach immobilizing a capture antibody to a substrate (well of a microtiter plate), adding sample, then adding detection antibody for a different epitope than the first antibody, the complex detected to indicate presence of the targeted laminin.
See also Marchini et al., EP 3657172A1 also acknowledge ELISA assay as a well known technique for measuring laminin, Marchini teach such methods involve antibodies which bind to laminin, such as monoclonal or polyclonal antibody, teaching such antibodies are also well known in the art and are commercially available, for example mouse monoclonal anti-laminin gamma-1, mouse monoclonal anti-laminin beta-1 antibody (see para [0030]).
See also regarding Marchini as cited, which acknowledges antibodies specific for laminin-beta-1 and laminin-gamma-1 are known and commercially available to those of ordinary skill in the art.
For all of these reasons, the claims alone or as an ordered combination, fail to include additional elements that are sufficient to either integrate the judicial exception into a practical application thereof or amount to significantly more than the judicial exception.
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 5-12 are rejected under 35 U.S.C. 103 as being unpatentable over Castillo et al., WO98/15179 in view of Marchini et al., EP 3657172A1, Burkin et al., WO2010/080581A2 and Saito et al., Overexpression of LARGE suppresses muscle regeneration via down-regulated of insulin-like growth factor 1 and aggravates muscular dystrophy in mice, Human Molecular Genetics, 23(17), (2014), p. 4543-4558.
Castillo teach a method (see page 63, lines 4 to page 64, line 24; page 65, lines 4-8; see also Castillo claim 29) for detection and quantitation of laminin, various types of ELISA can be used, Castillo specifically teaching two-site or sandwich type ELISA as preferred. Regarding this type of ELISA, Castillo teach immobilizing a capture antibody to a substrate (well of a microtiter plate), adding sample, then adding detection antibody for a different epitope than the first antibody, the complex detected to indicate presence/amount of the targeted laminin.
Castillo et al. fail to teach capture antibody specific for laminin beta-1 chain, detection antibody binding laminin gamma- chain. Further Castillo teach biological fluid samples, but fails to specifically teach micronized tissue sample.
Marchini et al. also acknowledge ELISA assay as a well known technique for measuring laminin, Marchini teach such methods involve antibodies which bind to laminin, such as monoclonal or polyclonal antibody, teaching such antibodies are also well known in the art and are commercially available, for example mouse monoclonal anti-laminin gamma-1, mouse monoclonal anti-laminin beta-1 antibody (see para [0030]). Marchini (see at para [0017]) further acknowledge that laminin molecules are heterometric proteins that contain alpha-chain, beta-chain and gamma-chain, that they are named according to their chain composition. See Marchini (para [0017]) teach the laminin family of glycoproteins are an integral part of the structural scaffolding in almost every tissue of an organism, and are secreted and incorporated into cell-associated extracellular matrices. Teaching (also para [0017]) laminin is vital for the maintenance and survival of tissues, for example Marchini teach LN111 is usually found in normal colorectal and breast tissues, and laminin alpha chains 2, 3, 6, are more abundant in human gastric mucosa. Machini teach defective laminins can cause muscles to form improperly, leading to a form of muscular dystrophy, lethal skin blistering disease (junctional epidermolysis bullosa) and defects of the kidney filter (nephrotic syndrome).
Burkin et al. teach (see page 22, 3rd full paragraph) laminin 111 (alpha-1, beta-1, gamma-1) is the predominant isoform found in developing skeletal muscle, 211 (alaph-1, beta-1, gamma-1) as the predominant form found in differentiated skeletal muscle. Burkin et al. teach Merosin deficient congenital muscular dystrophy (MDC1A) is the most common type of congenital muscular dystrophies (accounting for 30-40% of CMDs), that MDC1A is caused by mutation in the lama2 gene which encodes the laminin alpha-2 chain. Burkin teach (page 52, Example 3) ELISA to detect human laminin (namely, laminin alpha-2 antibody). Burkin further teach detecting laminin for the purpose of investigating the therapeutic effect of valproic acid (treating MDC1A).
Saito, at page 4544, col. 2, para 1, is consistent with Burkin et al. regarding MDC1A. See at page 4555, col. 2, para 2, regarding immunoassays (western blot, blot overlay, ELISA), Saito teach samples that are tissue samples treated by homogenization (muscle samples were homogenized, homogenized samples reading on “micronized samples”, see as supported by originally filed specification at page 4, para [0007] “preparing the micronized mixture may include homogenizing the tissue sample with a homogenization buffer”, see also para [0030]).
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 the laminin sandwich ELISA of Castillo et al. in order to target laminin isoforms 111 and 211, specifically to have modified the ELISA in order to immobilize anti-laminin-beta 1 chain antibody, and to have provided as the detection antibody, anti-laminin-gamma 1 chain antibody (as in Marchini), one motivated to monitor these particular isoforms in an effort to evaluate therapeutics for MCD1A (see Burkin and Saito). Specifically, it was known from the cited art (Burkin for example, also Saito) that these isoforms have the beta-1 and gamma-1 region present and available for detection.
Further one having ordinary skill would have been motivated to have provided antibodies targeting the beta-1 and gamma-1 regions as an obvious matter to try, namely by selecting from a finite number of art recognized suitable and predictable solutions known in the art for detection of laminin by immunoassay such as ELISA, see for example, Marchini, which teaches such antibodies are also well known in the art and are commercially available for detection of laminin, Marchini give specific examples, mouse monoclonal anti-laminin gamma-1, mouse monoclonal anti-laminin beta-1 antibody (see para [0030], Marchini).
One having ordinary skill in the art would have had a reasonable expectation of success because two antibody sandwich ELISA methods for detecting laminin were well known in the art before the effective filing date of the claimed invention (based on the cited art detailed above), and because the antibodies were known and available (one would expect success using reagents for their art recognized purpose), and further, one would have had a reasonable expectation of success using the particular species of known and commercially available antibodies to target isoforms 111 and 211 because each of these isoforms was known to have beta-1 and gamma-1 chain structures (so it would be logical to target these specifically).
Further, it would have been prima facie obvious to one having ordinary skill in the art to have performed the ELISA (as taught by Castillo and the cited art, for detection of isoforms 111 and 211) on tissue homogenate (i.e., a micronized sample) as an obvious matter of a known sample for its art recognized purpose (applying a known technique to a known methods), see for example Saito (which is consistent with Burkin), Saito teach tissue homogenate for the detection of laminin, this is a sample recognized to be reflective of this targeted analyte. One having ordinary skill in the art would have had a reasonable expectation of success using a sample known to contain the target for monitoring the targeted analyte, and further one having ordinary skill would have had a reasonable expectation of success given that these samples are suitable for immunoassays such as ELISA (able to perform ELISA on such samples, for detection of laminin, see Saito).
Claim 1 further recites “wherein the presence of the complex indicates presence of the target antigen with intact tertiary structure in the micronized tissue sample, and absence of the complex indicates absence of the target antigen with intact tertiary structure in the micronized tissue sample”, the “wherein” clause reads as a result which naturally follows as a result of the combination of the recited claimed elements/steps. As cited in detail above, the combination of the cited art is teaching a method comprising the same order of steps and same binding reagents as presently claimed. As a result, it would be expected that the combination of the cited art would similarly result in detection of the presence or absence of intact tertiary structure as claimed, particularly since the antibodies target two separate structures, namely the beta-1 and gamma-1 chains (both would necessarily be present when a positive result detected, since one antibody target beta-1 and one targets gamma-1).
Regarding claim 2, the combination of the cited art as detailed above targets antigens 211 and 111, as claimed.
Regarding claim 3, the combination the cited art above addresses determining concentration (see Castillo cited in detail above).
Regarding claims 5-6, see the combination of the cited art addresses detecting the presence of the antigen, i.e., detection/quantitating, and as such appears to address determining, based on concentration, pass or fail (present or not, for example see Castillo end of page 66 to page 67, compare to control tissue).
Regarding claim 7, see Castillo, for example at page 63-64, the method comprising washing the substrate with Tris-buffered saline containing Tween-20® (polysorbate 20).
Regarding claim 8, see Castillo et al. at page 64, lines 15-16, spectrophotometer to detect.
Regarding claim 9, the order of adding the capture antibody to substrate, adding the micronize sample, adding the detection antibody, is addressed by the combination of the cited art above (see as detailed above).
Regarding claim 10-12, see Saito et al. at page 4551, col. 1, para 1, MDC1A is a multi-organ disorder involving brain, eye and peripheral nerves, as well as skeletal and cardiac muscles.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have relied on sample comprising nerve tissue (claim 10) or for example skeletal tissue or cardiac (claims 11 and 12), when evaluating 211 and 11 related to MDC1A because it was known at the time that MDC1A involves peripheral nerve tissue as well as skeletal and cardiac tissue (obvious matter of a known technique applied to a known method, these is an art recognized sample sources expected to exhibit laminin expression). One having ordinary skill in the art would have had a reasonable expectation of success detecting in a sample known to exhibit laminin related to MDC1A.
Although claim 10 is amended to recite the wherein clause, namely “wherein the method assesses the potency of the nerve tissue for implantation”, the claims do not clearly recite any particular active method step of determining detecting and indicating a tissue is suitable for implantation, or any step which amounts to detecting, and as a result of the detecting, implanting the tissue. The wherein clause reads as a natural conclusion of the detection, i.e., that in performing the claimed steps as taught by the prior art and achieving detection, one is necessarily achieving an assessment of potency for implantation (see e.g., para [0025] of the originally filed specification, nerve including one or more laminin isoforms as listed is considered to be potent).
Claim(s) 4 is rejected under 35 U.S.C. 103 as being unpatentable over Castillo et al., in view of Marchini et al., , Burkin et al., and Saito et al., as applied to claim 3 above, and further in view of Holvoet et al., US Patent No. 6,309,888 and Suovaniemi et al., US Patent No. 7,358,062.
Castillo et. al. and the cited prior art teach a method substantially as claimed, however, fails to teach comparing concentration to a predetermined threshold (i.e., passing or failing includes comparing to a threshold) (claim 4).
It is the case that threshold/cutoff values were routinely used in the prior art as a point of reference against which measured values of a biomarker may be compared, in order to objectively interpret the results of laboratory tests. Moreover, the cutoff level selected for an assay was recognized in the prior art to be a result effective variable in diagnostic testing, having effects on both assay sensitivity and specificity. In particular, there was a known trade-off between sensitivity and specificity, in that increasing the sensitivity by lowering the cutoff value decreases the specificity, and vice versa (see below regarding support for this).
For example, Holvoet et al. teach that the diagnostic accuracy of a test or assay, i.e. the ability of the test or assay to distinguish between patients having a disease, condition or syndrome from those that do not, is based on whether the patients have a clinically significant amount of an analyte. A “clinically significant” amount refers to an amount higher than a predetermined cut point or threshold value for that analyte. See column 8, lines 37-50. Changing this cut point or threshold usually changes the sensitivity and specificity of the diagnostic test. For example, if the threshold is lowered, sensitivity (true positive rate) will be increased while specificity (true negative rate) will be decreased. Similarly, raising the cut point will tend to decrease sensitivity and increase specificity (column 9, lines 5-33).
Suovaniemi et al. teach that the concept of cut-off values/thresholds in assays involving the determination of analyte concentrations is well known to the person skilled in the art, and it generally means a value or a set of values chosen as a limit between the reference values (normal values) and the abnormal values for the test in question. Such cut-off values are method-specific and depend on the specificity and sensitivity chosen for the test method. See column 6, lines 4-13.
Therefore, it would have been further obvious to one of ordinary skill in the art to employ a threshold value (namely compare detected complex to a threshold value) when performing the methods of the Castillo et al. and the cited art, in accordance with routine practice for methods of detecting analytes (as taught by Holvoet and Suovaniemi). One would be motivated to do this in order to provide an objective means of successfully evaluate therapeutics for MCD1A. One having ordinary skill in the art would have a reasonable expectation of success comparing a threshold value because the prior art supports this is routine technique for objective analyses.
Claim(s) 13-19, 21-23, 25-27 and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Castillo et al., WO98/15179 in view of Marchini et al., EP 3657172A1, Burkin et al., WO2010/080581A2, Saito et al., Overexpression of LARGE suppresses muscle regeneration via down-regulated of insulin-like growth factor 1 and aggravates muscular dystrophy in mice, Human Molecular Genetics, 23(17), (2014), p. 4543-4558, Holvoet et al., US Patent No. 6,309,888 and Suovaniemi et al., US Patent No. 7,358,062.
Regarding independent claims 13-19, the combination of the cited art as detailed above (Castillo et al. in view of Marchini et al., Burkin et al. and Saito et al.) addresses preparing a micronized mixture from a tissue sample, such as tissue that is nerve tissue (see for example addressed previously at claim 10, Saito), immobilizing a first antibody to the substrate, adding the micronized sample to the substrate wherein binding occurs if target is present, adding secondary (detection) antibody binding a different second antigenic site (see the combination of the art, Castillo in view of Marchini, Burkin and Saito, capture antibody is anti-laminin-beta-1 and detection antibody is anti-laminin-gamma-1 antibody, binding and detecting the isoforms 111 and 211, the antibodies comprising mouse monoclonal antibodies, see Marchini et al.).
Specifically, copied from above, as with claim 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 the laminin sandwich ELISA of Castillo et al. in order to target laminin isoforms 111 and 211, specifically to have modified the ELISA in order to immobilize anti-laminin-beta 1 chain antibody, and to have provided as the detection antibody, anti-laminin-gamma 1 chain antibody (as in Marchini), one motivated to monitor these particular isoforms in an effort to evaluate therapeutics for MCD1A (see Burkin and Saito). Specifically, it was known from the cited art (Burkin for example, also Saito) that these isoforms have the beta-1 and gamma-1 region present and available for detection.
Further one having ordinary skill would have been motivated to have provided antibodies targeting the beta-1 and gamma-1 regions as an obvious matter to try, namely by selecting from a finite number of art recognized suitable and predictable solutions known in the art for detection of laminin by immunoassay such as ELISA, see for example, Marchini, which teaches such antibodies are also well known in the art and are commercially available for detection of laminin, Marchini give specific examples, mouse monoclonal anti-laminin gamma-1, mouse monoclonal anti-laminin beta-1 antibody (see para [0030], Marchini).
One having ordinary skill in the art would have had a reasonable expectation of success because two antibody sandwich ELISA methods for detecting laminin were well known in the art before the effective filing date of the claimed invention (based on the cited art detailed above), and because the antibodies were known and available (one would expect success using reagents for their art recognized purpose), and further, one would have had a reasonable expectation of success using the particular species of known and commercially available antibodies to target isoforms 111 and 211 because each of these isoforms was known to have beta-1 and gamma-1 chain structures (so it would be logical to target these specifically).
Further, it would have been prima facie obvious to one having ordinary skill in the art to have performed the ELISA (as taught by Castillo and the cited art, for detection of isoforms 111 and 211) on tissue homogenate (i.e., a micronized sample) as an obvious matter of a known sample for its art recognized purpose (applying a known technique to a known methods), see for example Saito (which is consistent with Burkin), Saito teach tissue homogenate for the detection of laminin, this is a sample recognized to be reflective of this targeted analyte. One having ordinary skill in the art would have had a reasonable expectation of success using a sample known to contain the target for monitoring the targeted analyte, and further one having ordinary skill would have had a reasonable expectation of success given that these samples are suitable for immunoassays such as ELISA (able to perform ELISA on such samples, for detection of laminin, see Saito).
Claim 1 differs from independent claim 13 in that claim 13 also recites tissue sample that is nerve tissue. Castillo et al. fails to specify tissue that is nerve tissue sample, and further the combination of the cited art fails to teach comparing the complex to a threshold level.
Saito et al. at page 4551, col. 1, para 1, in addition to citations above also teaches that MDC1A is a multi-organ disorder involving brain, eye and peripheral nerves, as well as skeletal and cardiac muscles.
It would have been further obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have relied on sample comprising nerve tissue when evaluating 211 and 111 related to MDC1A because it was known at the time that MDC1A involves peripheral nerve tissue as well as skeletal and cardiac tissue (obvious matter of a known technique applied to a known method, these is an art recognized sample sources expected to exhibit laminin expression). One having ordinary skill in the art would have had a reasonable expectation of success detecting in a sample known to exhibit laminin related to MDC1A.
Regarding the limitations recited at the preamble, the method of detecting “for implantation”, Applicant is reminded that the normal purpose of a claim preamble is to recite the purpose or intended use of the claimed invention. Such statements merely define the context in which the invention operates and usually will not limit the scope of the claim (MPEP 2111.02 and DeGeorge v. Bernier, Fed. Cir. 1985, 226 USPQ 758, 761 n.3).
In the instant case, the statements in the preamble do not provide antecedent basis for terms in the body of the claim, and are not essential to understand the limitations or terms in the body of the claim. The claims do not include, for example, active method steps in which a step of implantation is performed For these reasons, the preamble may be reasonably interpreted simply as a referring to the intended use of the recited detection method.
In the present case, the combination of the cited art addresses a method performing the active method steps as recited, the method detecting at least presence of laminin 111 and 211. As a result, since the method detects 111 and 211 consistent with the methods as presently claimed, it would be expected capable of achieving the same intended use, i.e., in detecting the same target, it would necessarily follow that the nerve having the same detected target be tissue sample similarly “for implantation”.
Claim 13 further recites at the preamble that the method claimed is intended for “detecting an active laminin protein”. As noted in detail previously above, the combination of the cited art is teaching the same order of method steps and same reagents. As a result, it would necessarily follow that the method as taught by the cited prior art similarly detect laminin considered to be “active laminin” as claimed (isoforms 211 and 111 notably are claimed species which appear to correlate with what applicant considers to be “active” isoforms, see further para [0022], Applicant’s originally filed specification appears to identify laminins (the family of proteins) as “active components”). As a result, the cited prior art method, detecting laminin, reads on detecting “active laminin” as claimed.
Regarding the amendment to claim 13 to recite, namely comparing the detected complex to a threshold concentration level, it is the case that threshold/cutoff values were routinely used in the prior art as a point of reference against which measured values of a biomarker may be compared, in order to objectively interpret the results of laboratory tests. Moreover, the cutoff level selected for an assay was recognized in the prior art to be a result effective variable in diagnostic testing, having effects on both assay sensitivity and specificity. In particular, there was a known trade-off between sensitivity and specificity, in that increasing the sensitivity by lowering the cutoff value decreases the specificity, and vice versa (see below regarding support for this).
For example, Holvoet et al. teach that the diagnostic accuracy of a test or assay, i.e. the ability of the test or assay to distinguish between patients having a disease, condition or syndrome from those that do not, is based on whether the patients have a clinically significant amount of an analyte. A “clinically significant” amount refers to an amount higher than a predetermined cut point or threshold value for that analyte. See column 8, lines 37-50. Changing this cut point or threshold usually changes the sensitivity and specificity of the diagnostic test. For example, if the threshold is lowered, sensitivity (true positive rate) will be increased while specificity (true negative rate) will be decreased. Similarly, raising the cut point will tend to decrease sensitivity and increase specificity (column 9, lines 5-33).
Suovaniemi et al. teach that the concept of cut-off values/thresholds in assays involving the determination of analyte concentrations is well known to the person skilled in the art, and it generally means a value or a set of values chosen as a limit between the reference values (normal values) and the abnormal values for the test in question. Such cut-off values are method-specific and depend on the specificity and sensitivity chosen for the test method. See column 6, lines 4-13.
Therefore, it would have been further obvious to one of ordinary skill in the art to employ a threshold value (namely compare detected complex to a threshold value) when performing the methods of the Castillo et al. and the cited art, in accordance with routine practice for methods of detecting analytes (as taught by Holvoet and Suovaniemi). One would be motivated to do this in order to provide an objective means of successfully evaluating therapeutics for MCD1A. One having ordinary skill in the art would have a reasonable expectation of success comparing a threshold value because the prior art supports this is routine technique for objective analyses.
Regarding claim 21, see Castillo’s ELISA comprising adding one or more detection reagents (see page 64, regarding details specific tot the ELISA, adding substrate, for example).
Regarding claim 22, Castillo further teach (page 53, line 22) examples of suitable enzyme labels for detection, including HRP.
Regarding claim 23, the combination of the cited art teaches preparing micronized sample by homogenation using a homogenizing buffer (see as cited in detail previously above, Saito).
Regarding claims 25-27, see the cited art and rationales as detailed previously above, the combination of the cited art is teaching a system (ELISA) for binding laminin (active laminin, as presently claimed), the system comprising anti-laminin-beta-1 capture antibody and anti-laminin-gamma-1 detection antibody, enzyme label (such as HRP).
Regarding claim 29, see further page 27, Castillo also teach their ELISA methods performed using a microplate reader (line 11, for example, the ELISA for detecting laminin bound AB protein of Alzheimer’s disease).
Regarding claim 30, Castillo et al. further teach providing their diagnostic assays in the form of a kit (see for example, page 65, line 8, page 66, line 23). Given broadest reasonable interpretation, the combination of Castillo et al. and the cited art addresses the claimed kit, see specifically the claim merely recite “kit for carrying out the method according to”, the claim fails to clearly identify any particular specific or limiting kit components.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Castillo et al., Marchini et al., Burkin et al., Saito, Holvoet et al. and Suovaniemi, as applied to claims 23 and 25 above, and further in view of Harlow and Lane, Antibodies: A Laboratory Manual (1988) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pg. 321 and Chapter 14 (59 pages).
Castillo et al. and the cited prior art teach a method substantially as claimed, see as cited previously above. Regarding claim 20, see further Castillo at the end of page 53 to page 54, Castillo teach detection by comparison of extent of enzymatic reaction of a substrate with similarly prepared standards (referring to reference standards, see Castillo references Harlow and Lane).
However, Castillo et al. does not clearly teach the method preparing and analyzing laminin reference standards (comprising specific laminin isoforms, i.e., antigens).
However, see Harlow and Lane, at Chapter 14, page 570, Harlow and Lane teach for detection and quantitation by antibody capture assays, comparing to standard curves using known concentrations of antigen (see paragraph 3). See at page 573, Harlow and Lane teach preparing serial dilutions of each antigen test solution, to determine amounts, compare measured values to those obtained using known amounts of pure antigen in a standard curve.
When performing and ELISA for specific laminin isoforms, as taught by Castillo et al. and the cited prior art, it would have been further prima facie obvious to have modified the method to prepare and analyze laminin reference standards, including the specific laminin isoforms, in order to quantitatively determine the amount of laminin isoform in the sample (Harlow and Lane). One having ordinary skill in the art would have had a reasonable expectation of success preparing and analyzing such standards because Castillo specifically acknowledge comparing to prepared standards, and because one would expect success performing a known technique for making an antibody binding assay quantitative (the ELISA of Castillo being an antibody binding assay intended for determining a quantitative result).
Claims 24 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Castillo et al., Marchini et al., Burkin et al., Saito, Holvoet et al. and Suovaniemi, as applied to claims 23 and 25 above, and further in view of Dardenne et al., FR2830451A1.
The combination of the cited art teach a method substantially as claimed, including a step of homogenizing sample with a homogenization buffer (see Saito, samples disrupted with polytron followed by Dounce homogenization in 50 mM Tris-HCL).
Dardenne et al., English translation at page 8, teaching a technique for tissue homogenization, tissue homogenized in PBS, containing 0.4 M NaCl, 0.05% Tween-20, 0.5% BSA, preparing sample for assay that is an ELISA.
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 the method as taught by Castillo and the cited art, to have homogenized tissue samples using the buffer taught by Dardenne (comprising polysorbate-20) as a simple modification of one art recognized buffer to homogenize tissue for another, both known in the art for preparing a tissue sample for detection by way of ELISA. One having ordinary skill in the art would have had a reasonable expectation of success because the combination of the cited art is directed toward detecting laminin in a tissue sample by ELISA, and Dardenne’s buffer is for homogenizing a tissue sample for ELISA.
Regarding the system claims (claim 28), as discussed previously above, regarding the claimed system, Castillo and the combination of the cited art teach an ELISA system and method substantially as claimed. It would have been further prima facie obvious to have modified the system as taught by Castillo and the cited art, to have provided with the ELISA system a buffer to homogenize tissue samples, specifically comprising the composition of Dardenne because the cited prior art (e.g., Saito) teach the samples containing the targeted analyte (laminin isoforms 111 and 211, of the combination of the cited art) are tissue samples. As a result, it would be obvious to further provide the buffer to prepare samples to be tested with the system. Further, to have provided the buffer of Dardene because Dardene’s buffer is an art recognized buffer to homogenize tissue in preparation for an ELISA. One having ordinary skill in the art would have had a reasonable expectation of success because the combination of the cited art is directed toward detecting laminin in a tissue sample by ELISA, and Dardenne’s buffer is for homogenizing a tissue sample for ELISA
Response to Arguments
Applicant's arguments filed 02/05/2026 have been fully considered but they are not persuasive.
Regarding remarks page 9, the previous rejections of claims 4 and 6 under 35 U.S.C. 112(b) are withdrawn, the rejection of claim 4 under 35 U.S.C. 101 is withdrawn (see as indicated in detail above).
Regarding the rejection of claims under 35 U.S.C. 103, Applicant argues the cited prior art does not teach all the features of independent claim 1, that Castillo discloses various types of ELISA assays for use to determine differences in specific laminin fragments to search as diagnostic markers to follow progression on a live patient during progression of disease (remarks pages 10-11). Applicant argues Castillo is silent as to the specific capture antibodies and silent as to micronized tissue samples. Applicant disagrees with the combination of the additionally cited prior art (remarks page 11). Applicant asserts that even if it would have been obvious to try antibodies targeting the beta-1 and gamma-1 regions, the cited prior art does not teach or suggest the specific aspects and order of the method of claim 1 in that it fails to teach adding micronized tissue sample to the substrate containing the capture antibody, performing the method and detecting in the micronized sample.
However, Applicant’s remarks are not persuasive because it is the combination of the cited art which establishes obviousness. Specifically, although Castillo teach biological fluid samples, and fails to specifically teach micronized tissue sample, there is motivation to perform the assay for detection relevant to MDC1A (see for, example cited in detail above, Burkin et al. and Saito et al.), and each of those references support detecting in homogenized tissue sample, which reads on micronized sample as claimed.
As a result, Applicant’s remarks are not persuasive.
Conclusion
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.
Correspondence
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677