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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/26/2026 has been entered.
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 1-11 and 13-30 are pending, claims 1, 4, 10, 11, 13, 15, 23 and 25 are amended, claim 12 is canceled, no claims are withdrawn. Claims 1-11 and 13-30 are examined below.
Withdrawn Objections/Rejections
The previous rejection of claim 4 under 35 U.S.C. 101 is withdrawn in response to Applicant’s amendments to the claims.
The previous rejections of claims under 35 U.S.C. 103 are withdrawn in response to Applicant’s amendments to the claims and in light of new search and consideration upon RCE.
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 13-30 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 13-25 use the terminology “active laminin”, the claim language is indefinite because there is no clear or limiting definition in the originally filed specification regarding how “active laminin” is defined such that would provide understanding for what structure is considered to be structure that is “active”, however, based on the specification at para [0020], Applicant’s specification appears to support that “active” laminin is laminin that results or promotes regeneration (see para [0020], Active components in a tissue graft that would result in or promote regeneration). The claims also use the terminology “intact” laminin which appears to reference intact tertiary structure. It is unclear if “active” laminin is the same as “intact” laminin, which is laminin have the alpha, beta and gamma chains, and that promotes regeneration, or if there is some other meaning encompassed by “active” beyond this species. Clarification is necessary.
Claim 19 recites “anti-laminin gamma-1 antibody is biotinylated anti-h/r/ laminin gamm-1 Purified Mouse Monoclonal IgG”, it is not readily clear what is “anti-h/r/ laminin gamm-1” antibody, for example, it is not clear what structure is specific to these antibodies. Although the specification does disclose an example of what Applicant considers to be antibody that meets this limitation (clone D18), there is no clear indication what other antibodies are “anti-h/r/ laminin gamma-1” and this language does not appear to be merely any anti-laminin gamm-1 antibody.
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 5-11 are rejected under 35 U.S.C. 103 as being unpatentable over Deister et al. US PG Pub No. 2017/0249498A1 in view of Lei et al., Identification of Extracellular Matrix Components and Biological Factors in Micronized Dehydrated Human Amnion/Chorion Membrane, Advances in Wound Care, 6(2), (2017), p. 43-53, Means et al., A Multicenter, Prospective, Randomized, Pilot Study of Outcomes for Digital Nerve Repair in the Hand Using Hollow Conduit Compared With Processed Allograft Nerve, Hand, 11(2), (2016), p. 144-151, Chen et al., Laminin γ1 is critical for Schwann cell differentiation, axon myelination, and regeneration in the peripheral nerve, 163(4), (2003), p. 889-899, Castillo et al., WO98/15179 (cited previously), Marchini et al., EP 3657172A1 and AxoGen, Advance Nerve Graft, Instructions for Use, https://axogeninc.eu/wp-content/uploads/2019/02/Avance-Nerve-Graft-Instructions-for-Use-English.pdf, (2019), (2 pages).
Deister et al. suggest that the quantity of accessible laminin is a key bioactive substance for fostering neurite regeneration in a nerve graft (see para [0019], “the greater the quantity and accessibility of the bioactive scaffold (laminin-coated endoneurial tube geometry) present in the graft, the greater the bioactivity of the graft. The reason is that more bioactive scaffold provides more growth structures for axons and Schwann cells to extend onto.”, see also para [0089]). Deister teach IHC, staining for laminin (para [0020]) to assess the structural integrity of a processed nerve allograft (para [0025]).
From Deister et al., it is understood that greater quantity of laminin is associated with a better nerve allograft (greater laminin, more bioactive scaffold, more growth structures for axons and Schwann cells to extend to). This is considered an assessment (quality control) of a nerve graft tissue’s regenerative capacity, considering that regenerative capacity is its ability to regrow or replace lost or damaged tissue, specifically indicating those tissue specimens that are considered suitable.
Deister et al. teach nerve graft is a processed nerve allograft (human) intended for surgical repair of peripheral nerve discontinuities to support regeneration across the defect (para [0031]), the allografts serve to provide surgeons with a readily available nerve graft to use for repair.
Although Deister et al. is teaching a quantitative assay for assessing regenerative capacity of a nerve tissue, specifically by assaying for laminin in nerve graft tissue, Deister et al. fails to teach the assay is an ELISA (Deister performing IHC), performed by immobilizing a capture antibody configured to bind laminin beta-1 chain to a substrate, adding micronized tissue sample from the nerve tissue to the substrate containing capture antibody, adding detection antibody configured to bind laminin gamma-1 chain. Deister et al. also fails to teach the assay detects target antigen with intact tertiary structure, and fails to teach upon determining intact tertiary structure, packaging the nerve tissue for distribution as a nerve graft.
In addition to IHC for quantitative determination of laminin, see also the prior art recognized the use of ELISA performed on micronized tissue to assess matrix components including laminin (see Lei et al. abstract, page 45, col. 2, para 3).
Means et al. teach that intact laminin in processed nerve allograft offer axon support and guidance cues not found in hollow conduit (see page 45, col. 1, para 2). As such, those of ordinary skill in the art before the effective filing date of the claimed invention understood the importance of intact laminin in processed nerve allografts.
Chen et al. teach that laminin γ1 is critical for Schwann cell differentiation, axon myelination, and regeneration in the peripheral nerve (see title and abstract, and also page 894, col. 2, last full paragraph, page 897, col. 1, para 1, and also page 895, col. 1, para 1 that laminin γ1 affects capacity of axons to regenerate after injury).
Castillo also 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, teaching that 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 (biotinylated antibody) for a different epitope than the first antibody, the complex detected to indicate presence/amount of the targeted laminin.
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.
AxoGen teach nerve grafts are processed in controlled environments using methods designed to prevent contamination and cross contamination of tissue (see page 2, middle column, “processing”), the graft is processed, and after processing is sized, packaged and sterilized (see also last paragraph, “How Supplied”).
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 Deister et al. in order to quantitatively detect laminin by performing ELISA on micronized tissue sample from the nerve graft in place of the IHC performed in Deister, for example as in Lei et al. (also Castillo and Marchini, teaching ELISA for laminin), namely using protocols as described Castillo (e.g., as described above, comprising capture and detecting antibody to detect laminin), as a simple substitution of one art recognized quantitative assay technique for detecting a tissue expressed laminin protein for another. In particular, the prior art contained the base method of detecting laminin containing specimen to indicate processed nerve allograft suitable for implantation (for nerve regeneration, see Deister described above). Each of IHC and quantitative ELISA (ELISA performed on micronized portion of a tissue specimen) were assay techniques known to those of ordinary skill in the art for determining the amount of a protein in a tissue specimen (see e.g., Deister, Lei et al.). One having ordinary skill in the art would have found it obvious to have substituted ELISA for IHC and the results would have predictably achieved determination of laminin containing allograft specimens.
One having ordinary skill in the art would have a reasonable expectation of success because Lei (as well as Marchini) specifically disclose the use of this type of ELISA for determining laminin in micronized tissue specimen. Both techniques achieve the same result, which is measurement of laminin in a tissue specimen. Additionally, one would expect success as the prior art (Marchini et al.) also acknowledges ELISA assay as a well-known technique for measuring laminin.
Further, when performing the ELISA to detect laminin, it would have been prima facie obvious when detecting in processed nerve allografts intended for implantation to target and detect laminin that is intact laminin, because Means et al. teach intact laminin in processed nerve allograft offer axon support and guidance cues for regeneration, and further that when detecting intact laminin, to specifically detect laminin at the gamma-1 chain, as the prior art recognized gamma-1 as critical for Schwann cell differentiation, axon myelination and regeneration in peripheral nerve (Chen et al.). As such, one of ordinary skill in the art would appreciate the importance of gamm-1 chain present on intact laminin to the ability of nerve tissue to regenerate and be usable for implantation as a nerve graft.
As such, it would have been prima facie obvious to have used as capture antibody in the ELISA, anti-beta1 chain antibody and as detection antibody, anti-gamma-1 antibody to ensure gamma-1 containing intact heterodimer present in the tissue selected to be used/intended for implantation/repair of nerve. Specifically, each of mouse monoclonal anti-laminin gamma-1, mouse monoclonal anti-laminin beta-1 antibody were known to those of skill in the art and commercially available (Marchini et al.), the modification, selecting beta-1 and gamma-1 as capture and detection antibody, further considered obvious to try, namely selecting from a finite number of identified predictable solutions (the heterotrimer known to contain alpha, beta and gamma chain, and further the art directing one to detect for gamma-1 chain when detecting suitable nerve tissue).
Further, there are a finite number of known domains on the targeted intact laminin for detection, with particular direction in the art when interested in suitable nerve allograft to target gamma-1. The antibodies to these particular domains are known and commercially available to those having ordinary skill in the art (Marchini). As a result, one having ordinary skill would have pursued the known potential solutions with a reasonable expectation of success, particularly with motivation (direction) to target and detect intact, gamma-1 containing laminin.
Finally, since Deister (and the combined cited prior art) teach methods directed at detecting laminin, indicating suitable tissue for implantation (allograft intended to regenerate damaged nerve), it would have been further obvious to process and package the laminin containing tissue specimens for the purpose of distribution, as in AxoGen, to prevent contamination and cross contamination of tissue, and provide the sized, packaged and sterilized product for surgical use (AxoGen). One having ordinary skill would have a reasonable expectation of success further packaging for distribution as in AxoGen because the purpose of Deister (and the combined cited prior art) is to provide/indicate tissue for implantation, and by packaging the processed specimen, as in AxoGen, the product is ready and available to surgeons for this intended purpose.
Regarding claim 2, the combination of the cited art would necessarily detect complex comprising target that includes one or more of the isoforms 111, 211, 311, 411, and 511 (each of which contains beta-1 and gamma-1 as part of the structure), as recited at claim 2, because the combination of the cited art directs one to use an anti-beta1 and anti-gamma1 antibody to bind and detect intact laminin (the intact form of laminin present in peripheral nerve tissue, intact form being the heterotrimer having gamm-1).
Regarding claim 3, the combination of the cited prior art is teaching quantitative determination, measuring concentration of targeted antigen.
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 addresses 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, also Deister et al. paras [0025] and [0068]).
Regarding claim 7, see as cited above, the combination of the cited- using the method/assay technique of Castillo, further 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, teach a 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, see as discussed above, the combination of the cited prior art is addressing assessing the quality (potency, i.e., ability) of the tissue for the purpose of implantation.
Regarding claim 11, see the combination of the cited art above is teaching peripheral nerve tissue (peripheral nerve allograft).
Claim(s) 2 is rejected under 35 U.S.C. 103 as being unpatentable over Deister et al., Lei et al., Means et al., Chen et al., Castillo et al. and Marchini et al. as applied to claim 1 above, and further in view of Talovic et al., Laminin Enriched Scaffolds for Tissue Engineering Applications, Advances in Tissue Engineering and Regenerative Medicine, 2(3), (2017), p. 194-200.
Although claim 2 is addressed previously above, in the interest of compact prosecution the claim is further addressed presently with additional prior art.
Regarding claim 2, the combination of the cited art teaches a method substantially as claimed, teaching detection of complex that is intact laminin indicative of tissue suitable for regeneration/implantation.
And although the use of antibodies against beta-1 and gamm-1 would necessarily detect isoforms having both of these chains (intact isoforms), the reference fails to specifically teach that the intact laminin is one of laminin 111, 211, 311, 411 and 511.
However, see Talovic et al., teaching Laminin 111, 211 are known in the art expressed in peripheral nerves (see page 194, col. 1, para 2). Talovic teach laminin 111 is crucial for maintaining nerve cells in peripheral nerves and serves as major substrate for neurite extension and axon growth, both in vivo and in vitro (page 195, col. 1, para 4).
It would have been prima facie obvious to one having ordinary skill in the art that the targeted laminin detected with the method of Deister et al. and the cited prior art is at least laminin 111 because it was recognized in the prior art that laminin 111 (and 211) are expressed in peripheral nerves, particularly 111 is known in the art as crucial for maintaining nerve cells in peripheral nerves (Talovic et al.). As such, it would be expected that the laminin be at least laminin 111.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Deister et al. in view of Lei et al., Means et al., Chen et al., Castillo et al. and Marchini et al. as applied to claim 1 above, and further in view of Holvoet et al. US Patent No. 6,309,888 (cited previously) and Suovaniemi et al., US Patent No. 7,358,062 (cited previously).
Regarding claim 4, Deister et al. and the cited prior art teach a method substantially as claimed, however fail to teach passing or failing the micronized tissue by comparing and determining whether the concentration is above a predetermined threshold concentration level.
It is the case that threshold/cutoff values are 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. As noted above, Deister suggest comparing a control, additionally Castillo teach comparing to a control (see Castillo end of page 66 to page 67, compare to control tissue, also Deister et al. paras [0025] and [0068]). 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.
It would have been further prima facie 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 Diester et al., (and the cited art, including Castillo et al.), 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 regenerative ability for a potential tissue allograft. 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) 13-18, 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Deister et al., Lei et al., Means et al., Chen et al., Castillo et al., Marchini et al. AxoGen, Talcovic et al., Laminin Enriched Scaffolds for Tissue Engineering Applications, Adv. Tissue Eng. Regen. Medicine, 2(3), (2017), p. 194-200, Holvoet et al. US Patent No. 6,309,888 (cited previously) and Suovaniemi et al., US Patent No. 7,358,062 (cited previously).
Claim 13 is substantially similar to claim 1, however claim 13 further recites the first and second antibody configured to bind “active laminin protein”, wherein the presence of complex indicates presence of one or more of laminin 111, 211, 311, 411, 511 isoforms with intact tertiary structure, the method comprising comparing to a predetermined threshold concentration level, determining sample passes at level exceeding the predetermined threshold, and further packaging the nerve tissue for distribution as a nerve graft. Claim 13 does not require the capture and detector antibody species of claim 1.
Deister et al. is as cited in detail previously above, Deister et al. suggest that the quantity of accessible laminin is a key bioactive substance for fostering neurite regeneration in a nerve graft (see para [0019], “the greater the quantity and accessibility of the bioactive scaffold (laminin-coated endoneurial tube geometry) present in the graft, the greater the bioactivity of the graft. The reason is that more bioactive scaffold provides more growth structures for axons and Schwann cells to extend onto.”, see also para [0089]). Deister teach IHC, staining for laminin (para [0020]) to assess the structural integrity of a processed nerve allograft (para [0025]).
From Deister et al., it is understood that greater quantity of laminin is associated with a better nerve allograft (greater laminin, more bioactive scaffold, more growth structures for axons and Schwann cells to extend to). This is considered an assessment (quality control) of a nerve graft tissue’s regenerative capacity, considering that regenerative capacity is its ability to regrow or replace lost or damaged tissue, specifically indicating those tissue specimens suitable.
Deister et al. teach nerve graft is a processed nerve allograft (human) intended for surgical repair of peripheral nerve discontinuities to support regeneration across the defect (para [0031]), the allografts serve to provide surgeons with a readily available nerve graft to use for repair.
Although Deister et al. is teaching a quantitative assay for assessing regenerative capacity of a nerve tissue, specifically by assaying for laminin in nerve graft tissue, Deister et al. fails to teach preparing a micronized mixture of nerve tissue sample, immobilizing a first (capture) antibody at a substrate, adding the micronized tissue sample from the nerve tissue to the substrate containing first antibody to bind first antigenic stie of active laminin, adding detection antibody configured to bind a second antigenic site of active laminin, where the presence of complex indicates presence of laminin 111, 211, 311, 411 or 511 with intact tertiary structure.
Although Deister do compare to a control (see cited previously above), because Deister fails to teach the same assay format (e.g., steps consistent with solid substrate assay such as an ELISA as indicated above), Deister fails to further teach comparing to a predetermined threshold concentration level, determining nerve tissue passes quality (suitable for implantation) when threshold concentration level is exceeded, and further packaging for distribution as a nerve graft.
Each of Lei, Means et al., Chen et al., Castillo et al., Marchini et al., and AxoGen are as cited in detail previously above.
In addition to IHC for quantitative determination of laminin, see also the prior art recognized the use of ELISA performed on micronized tissue to assess matrix components including laminin (see Lei et al. abstract, page 45, col. 2, para 3).
Means et al. teach that intact laminin in processed nerve allograft offer axon support and guidance cues not found in hollow conduit (see page 45, col. 1, para 2). As such, those of ordinary skill in the art before the effective filing date of the claimed invention understood the importance of intact laminin in processed nerve allografts.
Chen et al. teach that laminin γ1 is critical for Schwann cell differentiation, axon myelination, and regeneration in the peripheral nerve (see title and abstract, and also page 894, col. 2, last full paragraph, page 897, col. 1, para 1, and also page 895, col. 1, para 1 that laminin γ1 affects capacity of axons to regenerate after injury).
Castillo also 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, teaching that 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.
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.
AxoGen teach nerve grafts are processed in controlled environments using methods designed to prevent contamination and cross contamination of tissue (see page 2, middle column, “processing”), the graft is processed, and after processing is sized, packaged and sterilized (see also last paragraph, “How Supplied”).
Talovic et al., teaching Laminin 111, 211 are known in the art expressed in peripheral nerves (see page 194, col. 1, para 2). Talovic teach laminin 111 is crucial for maintaining nerve cells in peripheral nerves and serves as major substrate for neurite extension and axon growth, both in vivo and in vitro (page 195, col. 1, para 4).
Regarding claims 13-18, 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 Deister et al., with each of Lei, Means et al., Chen et al., Castillo et al., Marchini et al. for the same reasons as discussed previously above (thereby resulting in performing ELISA to detect in micronized tissue obtained from the tissue sample, performed using the ELISA technique as taught by Castillo, namely comprising capture antibody that is anti-beta1 capture antibody and anti-gamma1 detection antibody).
Although the combination of the cited prior art refers to the detection of “intact” laminin, and does not specifically use the word “active”, see the originally filed
Regarding the limitation wherein presence indicates presence of one of laminin 111, 211, 311, 411 and 511, the combination of the cited art would necessarily detect complex comprising target that includes one or more of the isoforms 111, 211, 311, 411, and 511 (each of which contains beta-1 and gamma-1 as part of the structure), as recited because the combination of the cited art directs one to use an anti-beta1 and anti-gamma1 antibody to bind and detect intact, i.e., active, laminin (the intact form of laminin present in peripheral nerve tissue, intact form being the heterotrimer having gamm-1).
Nonetheless, see also Talovic cited above, it would have been further prima facie obvious to one having ordinary skill in the art that the targeted laminin detected with the method of Deister et al. and the cited prior art is at least laminin 111 because it was recognized in the prior art that laminin 111 (and 211) are expressed in peripheral nerves, particularly 111 is crucial for maintaining nerve cells in peripheral nerves (Talovic et al.). As such, it would be expected that the laminin be laminin 111.
Further, as discussed previously above, it is the case that threshold/cutoff values are 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. As noted above, Deister suggest comparing a control, additionally Castillo teach comparing to a control (see Castillo end of page 66 to page 67, compare to control tissue, also Deister et al. paras [0025] and [0068]). 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.
As such, it would have been further prima facie 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 Diester et al., (and the cited art, including Castillo et al.), 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 regenerative ability for a potential tissue allograft. 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.
Finally, since Deister (and the combined cited prior art) teach methods directed at detecting laminin, indicating suitable tissue for implantation (allograft intended to regenerate damaged nerve), it would have been further obvious to process and package the laminin containing tissue specimens for the purpose of distribution as in AxoGen, to prevent contamination and cross contamination of tissue, and provide the sized, packaged and sterilized product for surgical use (AxoGen). One having ordinary skill would have a reasonable expectation of success further packaging for distribution as in AxoGen because the purpose of Deister (and the combined cited prior art) is to provide/indicate tissue for implantation, and by packaging the processed specimen, as in AxoGen, the product is ready and available to surgeons for this intended purpose.
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.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Deister et al., Lei et al., Means et al., Chen et al., Castillo et al., Marchini et al. AxoGen, Talcovic et al., Holvoet et al. and Souvaniemi et al, as applied to claims 18 above, Thermo Scientific, Design, visualize and detect immunostaining, https://documents.thermofisher.com/TFS-Assets/LSG/brochures/1601971-Antibody-Immunostaining-Guide.pdf, (2011), p.80 pages.
Regarding claim 19, the combination of the cited art teach a method substantially as claimed, however fails to teach the anti-laminin gamm-1 antibody is biotinylated anti-h/r laminin gamma-1 purified mouse monoclonal IgG (which see the originally filed specification, para [0082], Applicant identifies as Clone D18).
See Thermo Scientific page 30, table, clone D18 is an art recognized, commercially available monoclonal antibody (purified mouse monoclonal IgG).
It would have been prima facie obvious to one having ordinary skill to have used clone D18 as the anti-gamma-1 detection antibody (described by Applicant as an anti-h/r/ laminin gamma-1 Purified Mouse monoclonal IgG) as an obvious matter to try, namely selecting from a finite list of art recognized known and available commercial antibodies known for the purpose of binding and detecting gamma-1. Specifically, the prior art recognized commercially available antibodies, available for purchase and application for binding laminin gamma-1, D18 is one of those art recognized antibodies. One having ordinary skill would have found it obvious to select from those antibodies known and available for purchase, one further having a reasonable expectation of success relying on reagent known and available for its intended purpose (known to detect gamma-1).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Deister et al., Lei et al., Means et al., Chen et al., Castillo et al., Marchini et al. AxoGen, Talcovic et al., Holvoet et al. and Souvaniemi et al, as applied to claims 13 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) (cited previously).
The combination of the cited art teach a method substantially as claimed, see as cited previously above. However, Deister fails to teach preparing an analyzing laminin reference standards that are isoforms 111, 211, 311, 411 and 511.
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 Deister et al. 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 the prior art, for example, 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 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Deister et al., Lei et al., Means et al., Chen et al., Castillo et al., Marchini et al. AxoGen, Talcovic et al., Holvoet et al. and Souvaniemi et al, as applied to claims 13 above, and further in view of Dardenne et al., FR2830451A1 (cited previously).
Regarding claim 23, the combination of the cited art teaches preparing micronized sample (see for example Lei et al., as cited above, performing ELISA to detect in micronized specimen, see page 45, col. 2, para 2), however, does not directly teach micronized mixture includes homogenizing the nerve tissue sample with a homogenization buffer.
However, see for example 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 that the process of preparing micronized tissue include a homogenization buffer as an obvious matter of a known technique applied to a known process, specifically since the prior art supports preparing micronized sample for ELISA include homogenizing tissue in a buffer, see Dardenne et al.). The prior art contained the base method, of performing an ELISA on a micronized tissue specimen (e.g., Lei et al., Dardenne et al.), and the prior art contained the known technique applicable to this process, namely the technique of performing the process in a buffer. As noted Lei, who disclose performing an ELISA on micronized sample), is silent regarding the details of their process details for producing the sample. One having ordinary skill in the art would have recognized that applying the known technique, i.e., performing in homogenization buffer, would have yielded the predictable results of producing micronized tissue specimen for assay by ELISA. One having ordinary skill would have a reasonable expectation of success applying a known process for its intended purpose.
Claim(s) 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Lei et al. in view of Castillo et al. and Marchini et al.
Laminin ELISA kits for detecting laminin in tissue samples are known to those of ordinary skill in the art, see for example, Lei et al. teach an ELISA for detecting laminin (see e.g., page 45, col. 2, para 2, ).
However, Lei et al. fails to teach the assay is for active laminin, and as such fails to teach capture antibody that is beta-1 laminin and detection antibody that is gamm-1 laminin detection antibody (claim 25).
Castillo et al. also teach ELISA for detecting laminin, namely intact laminin (see for example at the claims 16 and 19, see also claim 6, laminin including intact laminin (intact laminin being the heterotrimer having alpha, beta and gamma chains).
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.
Regarding claims 25 and 26, it would have been prima facie obvious to have provided as capture antibody of the ELISA, anti-beta1 chain monoclonal antibody and as detection antibody, anti-gamma-1 monoclonal antibody in order to provide an ELISA for intact laminin (gamma-1 containing intact heterodimer). Specifically, each of mouse monoclonal anti-laminin gamma-1, mouse monoclonal anti-laminin beta-1 antibody were known to those of skill in the art and commercially available (Marchini et al.), the modification, selecting beta-1 and gamma-1 as capture and detection antibody, further considered obvious to try, namely selecting from a finite number of identified predictable solutions (the heterotrimer known to contain alpha, beta and gamma chain, and further the art directing one to detect for gamma-1 chain when detecting suitable nerve tissue).
Further, there are a finite number of known domains on the targeted intact laminin for detection, with particular direction (Castillo teach detecting intact) in the art for intact laminin (containing each of alpha, beta and gamma chain). The antibodies to these particular domains are known and commercially available to those having ordinary skill in the art (Marchini). As a result, one having ordinary skill would have pursued the known potential solutions with a reasonable expectation of success, particularly with motivation (direction) to target and detect intact, gamma-1 containing laminin.
Regarding claim 25, the claim recites at the preamble that the ELISA is intended for “detecting active laminin protein in a nerve tissue and for assessing regenerative capacity of the nerve tissue”, 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 present 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. For example, the claim is not directed to a method comprising steps of detecting, rather the claimed invention at claim 25 is directed to a product invention (ELISA system). For this reason, the preamble may be reasonably interpreted simply as referring to the intended use of the recited detection method.
Further, regarding the intended use, Lei et al. teaches using an ELISA system to detect laminin in a tissue sample by way of micronized sample; as such Lei supports that the ELISA as modified by Castillo is usable for the same intended use as presently claimed for detecting in nerve tissue (a solid specimen).
Additionally, the claim recites “wherein the formation of a complex of the capture antibody, a target antigen in a micronized sample of the nerve tissue
Regarding claim 27, Castillo further teach (page 53, line 22) examples of suitable enzyme labels for detection, including HRP.
Claim(s) 28 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Lei et al in view of Castillo et al. and Marchini et al., as applied to claim 25 above, and further in view of Dardenne et al. and Zuk et al., US Patent No. 4,208,479.
Regarding claim 25, the combination of the cited art teaches an ELISA intended for a micronized specimen (a micronized tissue specimen, see page 45, col. 2, para 2), however, does not directly teach micronized mixture produced using a homogenization buffer containing BSA and Tween®-20.
However, see for example 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.
However, Zuk et al. teach that in performing assays, it is convenient and to combine the necessary reagents together in a kit (column 22, lines 20-68 in particular). Zuk et al. further teach that this may improve assay accuracy.
It would have been prima facie obvious to one having ordinary skill in the art to provide with the ELISA as taught by Lei and Castillo, a homogenization buffer comprising Tween®-20 and BSA, as part of a system together (for example, as a kit), in order to prepare tissue for assay via ELISA, specifically Lei et al. teach micronized sample (tissue processed to form micronized sample since the ELISA is intended for detection of laminin in tissue sample), one motivated to provide the buffer with the ELISA for convenience and accuracy (Zuk et al.). One having ordinary skill in the art would have a reasonable expectation of success considering Lei supports that in order to test tissue by ELISA it is necessary to micronize the sample.
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). For the same reasons as applied to above (claim 28), it would have been additionally obvious to provide with the ELISA system a microplate reader.
Claim(s) 30 is rejected under 35 U.S.C. 103 as being unpatentable over Lei et al in view of Castillo et al. and Marchini et al., and alternatively, additionally Zuk et al.
Laminin ELISA kits for detecting laminin in tissue samples are known to those of ordinary skill in the art, see for example, Lei et al. teach an ELISA for detecting laminin (see e.g., page 45, col. 2, para 2, ).
However, Lei et al. fails to teach the assay is for active laminin, and as such fails to teach capture antibody that is beta-1 laminin and detection antibody that is gamm-1 laminin detection antibody (claim 25).
Castillo et al. also teach ELISA for detecting laminin, namely intact laminin (see for example at the claims 16 and 19, see also claim 6, laminin including intact laminin (intact laminin being the heterotrimer having alpha, beta and gamma chains). See further page 64, line 22-23, Castillo also teach providing their assay (ELISA) in the form of a kit.
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.
However, Zuk et al. teach that in performing assays, it is convenient and to combine the necessary reagents together in a kit (column 22, lines 20-68 in particular). Zuk et al. further teach that this may improve assay accuracy.
It would have been prima facie obvious to have provided a product (i.e., ELISA comprising the capture and detection antibodies as recited at claim 13) for the same reasons as discussed in detail previously above (see as discussed previously above at claim 25).
Claim 30 recites “a kit for carrying out the method” and is not limited to any particular structure reagents, the method of claim 13 reciting limitations specific to performing an ELISA for intact/active laminin (see discussed previously above). The ELISA as taught by Lei in view of Castillo and Marchini is usable to carry out detection as in claim 13, and as such addresses the claim, see further, regarding providing assay that is an ELISA, Castillo et al. also teach providing such an assay in kit form.
Nonetheless, see further Zuk, it would alternatively (or additionally) be obvious to provide the ELISA in the form of a kit for convenience and accuracy (see discussed previously above).
Response to Arguments
Applicant's arguments filed 06/26/2026 have been fully considered but they are not persuasive for the following reasons.
Regarding remarks at page 10-11, the rejection under 35 U.S.C. 101 is withdrawn in response to amendments to the claims.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant argues (remarks pages 12) that the number of references is evidence that the claims are non-obvious and patentable. This argument is not persuasive, particularly in light of the new grounds of rejection. Additionally, in response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991). In the present case, the number of references cited together supports the prima facie case of obviousness.
Regarding independent claim 1, Applicant argues that the previously cited prior art fails to disclose or suggest a method of performing quality control to assess regenerative capacity of a nerve tissue that includes performing an ELISA as claimed (remarks page 12). However, this argument is not persuasive, see new grounds of rejection set forth in detail above following an updated search and consideration upon Applicant’s filing RCE.
Similarly, at remarks pages 13-15 Applicant argues the rejection of claim 13, arguing that the cited art fails to teach the steps of the claim, specifically remarking that the preamble establishes the essential context for the entire method (remarks page 14), that the claim’s body is consistent with the preamble, the method for quality control to evaluate nerve tissue intended for implantation. See new grounds of rejection set forth in detail above, the rejection as amended addresses the amended claims and further, as a result of new search and consideration upon Applicant’s filing of RCE.
At remarks page 16, Applicant notes amendments to the claims to recite “active laminin” and “intact tertiary structure”, see amended grounds of rejection as detailed above, the cited prior art appears to address detecting the same laminin (intact, active laminin) for the purpose of assessing a tissue sample for possible implantation and its ability to successfully regenerate (see for example, Deister et al., cited in detail above).
Regarding remarks at page 17, that Holvoet and Suovaniemi teach threshold reference for the purpose of testing for disease, and not evaluating nerve tissue for implantation, this argument is not persuasive. Specifically, it is maintained that the ordinarily skilled artisan would appreciate that the concept/technique of relying on a threshold/cutoff is not limited to merely disease, but is a way to qualify a result, to determine/evaluate whether the observed outcome meets or exceeds predefined boundaries that mark a meaningful or significant change/outcome.
Regarding the remarks at page 17, specific to the previous motivation that is to “evaluate therapeutics for MDC1A”, this argument is not persuasive in light of the new grounds of rejection set forth in detail above.
Additionally, regarding remarks at page 18, see the new grounds of rejection above, newly cited prior art addresses further packaging the nerve tissue for distribution as a nerve graft.
Regarding claim 25, Applicant argues claim 25 should be allowable for similar reasons discussed above, however, as noted above, see new grounds of rejection.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677
Prosecution Insights