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 .
Status of the Claims/Application
Claims 22-23 are canceled. Claims 5, 7-13, 19 and 21 are currently amended. Claims 1-21 are currently pending and are under examination on the merit herein
Priority
The instant application 17/923,872 filled on 11/07/2022, is a 371 of PCT/US2021/031376 filed on 05/07/2021 and has a US Provisional application 63/022,372 filed on 05/08/2020 for which the instant application claims priority. The claims will be examined with an effective priority date of 05/08/2020.
Nucleotide and/or Amino Acid Sequence Disclosures
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification (pg. 3-31, 33-36, and 69) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (Figures 1B and 12B) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature or natural phenomenon without significantly more.
The claim is evaluated below using the “Subject Matter Eligibility Test for Products and Processes” flow chart in MPEP 2106 III.
Regarding claim 1,
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes, the claims are drawn to a process or method for determining the propensity or risk of a subject for having or developing an autoimmune disease or disorder based on the subjects C4A and C4B gene copy number, which is one of the four statutory categories.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature or natural phenomenon?
Yes, the claims recites a natural phenomenon limitation where in an increased dosage of the C4A and C4B of the subject relative to a reference indicates that the subject has a reduced propensity or risk for having or developing the autoimmune disease or disorder.
Step 2A, Prong Two: Does the claim recite additional elements that integrates the judicial exception into a practical application?
Yes, the claim also recites a method for detecting the C4A and C4B gene copy number. The measuring step is a data gathering step needed to apply the judicial exception and is therefore an insignificant extra-solution activity. See MPEP 2106.05(g)
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No, the method for measuring the C4A and C4B gene copy number for a subject is recited at a high level of generality, indicating that a well-understood, routine and conventional methods are being applied for the detection of the C4B and C4A gene copy numbers.
Regarding claims 2-3, and incorporating the analysis of claim 1, the claims merely adds a judicial exception (natural phenomenon) by reciting limitations; where for each C4B copy number, a greater number of C4A is associated with a significantly reduced propensity or risk, and for each C4A copy number, a greater C4B copy number is associated with more modestly reduced propensity or risk. The limitations of both claims do not otherwise change the analysis relative to claim 1.
Regarding claim 4 and 12, and incorporating the analysis of claim 1 above, claims 4 and 14 recites limitations for calculating the subject’s risk score, where the risk score is calculated as 2.3 times the number of C4A genes, plus the number of C4B genes in the subjects genome (a mathematical calculation) and the C4-derived risk score and/or joint C4A and C4B gene copy number is provided by performing computational analysis (a mathematical calculation). The limitations are a mere recitation of additional judicial exception (an abstract idea or mathematical calculation) and does not otherwise change the analysis relative to claim 1.
Regarding claims 5-6, and incorporating the analysis of claim 1 above, the claims recites limitations for calculating a subject’s joint C4A and C4B gene copy number by summing the C4A and C4B gene contents (a mathematical calculation) for each possible pair of two inherited C4 alleles (a natural product). The limitations are a mere recitation of additional judicial exceptions (mathematical calculation and natural product) and does not otherwise change the analysis of claim 1.
Regarding claims 7-8, and incorporating the analysis of claim 1 above, the claims recites limitations where the protective effect of the C4A copy number is increased in a male subject relative to a female subject (a natural phenomenon) and where the protective effect of the C4A copy number is increased in a subject of European ancestry relative to a subject of African ancestry (a natural phenomenon). The limitations are a mere recitation of additional judicial exceptions and do not otherwise change the analysis of claim 1.
Regarding claims 9-11, and incorporating the analysis of claim 1 above, the claims recites limitations where the autoimmune disease is systemic lupus erythematosus or Sjogren’s syndrome (natural phenomenon), the genome is characterized by whole genome sequencing (mere data gathering), and the sample comprises cells, plasma or cerebral spinal fluid (a natural product). The limitations are a mere recitation of additional judicial exceptions and do not otherwise change the analysis of claim 1.
Regarding claim 13, and incorporating the analysis of claim 1 above, the claim recites a limitation wherein computational analysis and/or an algorithm is applied for facilitating the determination of the subject’s propensity or risk (an abstract idea). The limitation is a mere recitation of additional judicial expectations and do not otherwise change the analysis of claim 1.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5-7, 9 , 11 , 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet. 2007 Jun;80(6):1037-54, herein further referred to as Yang et al and as evidenced by Kamitaki et al. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. 2020 Jun;582(7813):577-581, herein further referred to as Kamitaki et al.
Regarding claim 1, Yang et al. teaches a method for evaluating the risk is a subject developing an autoimmune disease such as systemic lupus erythematosus (SLE) by detecting the gene copy number (GCN) of C4A and C4B in the subject’s genome (Yang et al. pg. 1040 col 1 para 2) in a sample collected from the subject (Yang et al. Pg 1039 col 2 para 1 to pg. 1040 col 1 para 1), wherein an increase amount of C4A and C4B compared to a reference suggest that the subject is less susceptible to the autoimmune disorder (SLE) (Yang et al. pg. 1042 col 1 para 1-3 and Abstract).
Regarding claim 2, and incorporating the analysis of claim 1 above, Yang et al. teaches that the GCN varied from 2 to 6 for total C4, from 0 to 5 for total C4A and from 0 to 4 for C4B. Also, patients with SLE clearly had the GCN of total C4 and C4A shifting to the lower side. Indicating that a higher GCN of C4A was significant in reducing the risk of SLE especially when the subject had 2 or more C4A copies where the GCN of total C4 is greater than 5 copies (Yang et al. Abstract).
Regarding claim 3, and incorporating the analysis of claim 1 above, Yang et al. teaches that the risk of a subject having or developing SLE may be as a result of the GCN of C4A, C4B or both. Yang et al. teaches that higher the C4 and C4A GCN the less likely the subject is susceptible to SLE. Yang et al in Tab. 3 (Sibling 2) teaches a patient population where for each C4A, there is an increase in C4B GCN (GCN total for C4 is 6, for C4A is 2 and for C4B is 4).
Regarding claims 5-6, 13, Yang et al. teaches that the gene copy-number variation (CNV) of the total number of C4, C4A, C4B where determined and that the primary goal was to determine whether total (C4A plus C4B), C4a, and/or C4B CNV are genetic risk factors for SLE (Yang et al. pg. 1038 col 2 para 2). Long and short alleles of C4A and C4B were identified by Yang et al., page 1040, col 1). Yang et al teach x2 analysis was performed to determine the difference in total C4, C4A, and C4B gene CNV among various groups (Yang et al, page 1040, col 2).
Regarding claims 7, and incorporating the analysis of claim 1 Yang et al. teaches that SLE disease predominantly affects women of child-bearing age (Yang et al. pg. 1037 col 1 para 1). Yang et al. teaches of a decrease C4 GCN in female population with SLE which was attributed to a lower C4A GCN (Yang et al. pg. 1042 col 1 para 4 – col 2 para 2). Further, it is known that C4 is more protective in men than in women. Kamitaki et al. indicates that the effects of C4 alleles in lupus are stronger in men, indicating a larger C4 effects in men and that the stronger effect of C4 alleles in men relative to females could arise from a sex difference in C4 RNA expression, C4 protein levels or downstream responses to C4 (Kamitaki et al Abstract, pg. 10 ln 286-295 and pg. 11 ln 323-327). Also, C4A copy number is an inherent characteristic of the subject and as indicated by Kamitaki et al. C4 alleles acts more strongly in males than in females, and therefore a lower risk factors for males to have or to develop SLE (Kamitaki et al. pg. 1 para 1).
Regarding claim 9, and incorporating the analysis of claim 1, Yang et al. teaches that the autoimmune disease is SLE (Yang et al. Abstract).
Regarding claim 11, and incorporating the analysis of claim 1 above, Yang et al. further teaches that EDTA plasma was used as the sample from which C4 GCN was obtained (Yang et al. pg. 1039 col 2 para 2).
Claim(s) 1, 4, 8, 12 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Kamitaki et al. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. 2020 Jun;582(7813):577-581 herein further referred to as Kamitaki et al.
Regarding claims 1, 4, and 12, Kamitaki et al teach that C4 alleles increased risk for schizophrenia, generate a 7-fold variation in risk for lupus, and a 16-fold variation in risk for Sjogren’s syndrome. The alleles greatly reduced risk in lupus and Sjogren’s syndrome, wherein C4A protected more strongly than C4B. The C4 alleles acted more strongly in men than in women (Kamitaki et al., abstract). Kamitaki et al. teaches that logistic-regression analysis (a computational analysis) estimated the protection afforded by each copy of C4A was equivalent to that of 2.3 copies of C4B and that the C4-derived risk score is calculated as 2.3 times the number of C4A genes, plus the number of C4B genes, in the subject’s genome (Kamitaki et al. pg. 4 ln 114-117).
Regarding claim 8, Kamitaki et al. teach that combinations of C4B(s) and DRB1*03:01 allele dosages in African Americans showed that C4-B(S) allele consistently increased SLE risk regardless of DRB1*03:01 status, whereas DRB1*03:01 had no consistent effect when controlling for C4 (page 7, 2nd parag).
Claims 14-16 and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Quarticcio et al. Urgent avenues in the treatment of COVID-19: Targeting downstream inflammation to prevent catastrophic syndrome. Joint Bone Spine. 2020 May;87(3):191-193, as evidenced by WO’155, herein further referred to as Quarticcio et al.
Regarding claims 14-16 and 19, Quarticcio et al. teaches a method of treating inflammation associated to COVID-19 in a subject wherein an effective amount of Eculizumab is administered to the subject Quarticcio et al. pg. 192 Sec 5). WO’155 teaches that Eculizumab/Soliris is an FDA-approved compliment inhibitor that regulates C4 (WO’155 pg. 60 ln 13-17) that was used for treating subjects with schizophrenia.
Claim Rejections - 35 USC § 103
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.
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 10 is rejected under 35 U.S.C. 103 as being unpatentable over Yang et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet. 2007 Jun;80(6):1037-54 as applied to claim 1 above, and further in view of WO2017/132155 A1 herein further referred to as Yang et al. and WO’155 respectively.
The applied reference (WO’155) has a common inventor (McCarroll, Steven) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
As indicated above, Yang et al. teach the limitations of claim 1. However, Yang et al. do not teach whole genome sequencing.
Regarding claim 10, and incorporating the analysis of claim 1, Yang et al. teaches that TaqI genomic RFLP was performed employing specific probes corresponding to the genomic regions including C4 and the GCN of C4A and C4B were determined by PshAI-PvuII genomic RFLP to distinguish the C4A and C4B isotypic sites (Yang et al. pg. 1040 col 1 para 2). However, Yang et al. do not specifically teach whole genome sequencing.
WO’155 teaches that C4 alleles where imputed from SNP genotype can be analyzed and characterized by whole genome sequencing (WO’155 pg. 83 ln 2-16 and pg. 88 ln 10-16).
Therefore, it whole have been obvious before the effective filing date for one with ordinary skill in the art to modify the teachings of Yang et al. in view of WO’155 with a reasonable degree of predictable success to use a method of sequencing such as whole genome sequencing in order to determine or characterize the genome so as to obtain a GCN for C4, C4A and C4B. One would have done so because WO’155 teaches that whole genomic sequence can be used to identify SNP genotype.
Claim 17-18 is rejected under 35 U.S.C. 103 as being unpatentable over Quarticcio et al. as applied to claim 14 above, and further in view of Kamitaki et al.
As indicated above, Quarticcio teach the limitations of claim 14.
Regarding claims 17-18, Quarticcio teaches a patient male patient population as a predictive factor for patients with corona virus to be admitted to intensive care or death.
Quarticcio et al. does not specifically teach that the effective amount of C4 inhibitor is increased in a male subject relative to the amount of C4 inhibitor administered to a female subject.
Kamitaki et al. teaches that the effects of C4 alleles in lupus are stronger in men, indicating a larger C4 effects in men and that the stronger effect of C4 alleles in men relative to females could arise from a sex difference in C4 RNA expression, C4 protein levels or downstream responses to C4 (Kamitaki et al pg. 10 ln 286-295 and pg. 11 ln 323-327).
Therefore, it would have been obvious before the effective filing date for one with ordinary skill in the art to modify the teachings of Quarticcio et al. in view of Kamitaki et al. with a high degree of -----predictable success so as to administer an increased dose of the C4 inhibitor for the treatment of the COVID 19 inflammation as compared to the amount that will be administered to a female subject. As indicated by Kamitaki et al, male subjects generally show a higher C4 gene copy number than female subjects and therefore, to inhibit C4 in a male subject an increased amount of C4 inhibitor maybe required. Therefore, an ordinary artisan would have been able to recognize that administering an increased amount of the C4 inhibitor to a male subject with higher C4 GCN than relative to a female subject with lower C4 GCN would have been obvious to treat the individual with a COVID-19 associated inflammation.
Claims 20-21 are rejected under 35 U.S.C. 103 as being unpatentable Yang et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet. 2007 Jun;80(6):1037-54 and further in view of Wen et al. Clinical and laboratory evaluation of complement deficiency, Journal of Allergy and Clinical Immunology, Volume 113, Issue 4, 585 - 593, and Wang et al., Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to proteas-activated receptors 1 and 4, PNAS 2017 October 10, 2017, 14: 10948-10953, here in after referred to as Yang and Wen and Wang respectively.
Regarding claims 20-21, Yang teaches of subjects who have low C4 copy number and have SLE or are at risk of developing SLE (Yang Abstract) due to the low C4 copy number.
Yang does not teach a method for treating patients with SLE by administering a therapeutically effective amount to C4 agonist, activator or C4 supplementary agent.
Wen teaches a method for complement therapeutics in clinical practice where blood transfusion was use to replace the missing complement component. Wen also teaches treatment success in 2 SLE patients with C2 deficiency and several patients with factor H deficiency (Wen pg. 591 col 2 para 2).
Regarding recombinant C4a, Wang et al. teach that recombinant C4a can be made (Wang et al., page 10950, under C4a colocalizes with PAR1 and PAR4…”)
Therefore, it would have been obvious before the effective filing date for one with ordinary skill in the art to modify the teachings of Yang in view of Wen and Wang with high a high degree of predictable success to arrive at treatment of Yang’s SLE patient with low levels of C4 by administering a therapeutically effective amount of C4a protein. One would have done so because Yang teaches that SLE patients having higher levels of C4 have less severe disease and Wen and Wang show that one can treat patients that have low level of proteins with protein replacement therapy.
Conclusion
No claims allowed.
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/EMMANUEL LED YOUTCHOM PENDIE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647