DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election without traverse of Group I and the combination of rs1883832 and rs4810485 in the reply filed on December 22, 2025. Technically this reply is non-responsive because Applicants failed to elect an additional mutation for claim 6 (see page 6 of the Restriction/Election). However after further consideration, the examiner has decided to withdraw this requirement.
Claims 1-10, 12-20, and 22 are currently pending.
Claims 12-20 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 30, 2023.
Nucleotide and/or Amino Acid Sequence Disclosures
3. REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via EFS-Web or Patent Center as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via EFS-Web or Patent Center as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
I. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See sequences recited in Table 1.
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.
Claim Rejections - 35 USC § 101
4. 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 1-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite the following limitations:
-predicting that the subject will respond to treatment with a CD40-targeted active agent when the determined genotype of rs1883832 is homozygous for C or when the determined genotype of rs4810485 is homozygous for G;
-predicting that the subject will not respond to treatment with a CD40-targeted active agent when the determined genotype of rs1883832 is heterozygous or homozygous for T or when the determined genotype of rs4810485 is heterozygous or homozygous for T.
The instant claims recite a law of nature. The claims recite correlations between SNPs rs1883832 and rs4810485 and response to treatment with a CD40 targeted active agent. and SIRPα expression. These types of correlations are a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. The “predicting” step broadly encompasses an activity that can be performed in the human mind. For example, one may “predict” the subjects responsiveness to the CD40 target active agent by thinking about which alleles of the SNPs the subject has.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Claim 2 recites the following limitations:
-administering a CD40-targeted active agent to the subject when the determined genotype of rs1883832 is homozygous for C or when the determined genotype of rs4810485 is homozygous for G;
-administering a treatment to the subject that does not target CD40 when the determined genotype of rs1883832 is heterozygous or homozygous for T or when the determined genotype of rs4810485 is heterozygous or homozygous for T.
It is noted that a claim limitation can integrate a judicial exception by applying or using the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. However the treatment or prophylaxis limitation must be “particular”, i.e., specifically identified so that it does not encompass all applications of the judicial exceptions. While a “CD40-targeted active agent” is considered a “particular” treatment, “a treatment that does not target CD40” is not a “particular” treatment. The administration of “a treatment that does not target CD40” is instead merely instructions to “apply” the exception in a generic way. The claim broadly encompasses situations where the subject is given “a treatment that does not target CD40” and in those situations a “particular” treatment is not administered. Since claim 2 does not require administering a “particular” treatment in both situations, the claim does not recite any steps or elements that integrate the judicial exception so as to practically apply the judicial exception.
In addition to the judicial exceptions the claims require genotyping CD40 SNPs in a biological sample from a subject. This step is NOT considered to integrate the judicial exception into a practical application because it merely adds insignificant extra-solution activity (data gathering) to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims require genotyping CD40 SNPs in a biological sample from a subject. This step does NOT amount to significantly more because it simply appends well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The step is recited at a high level of generality. The genotyping step merely instructs a scientist to use any method to determine the alleles of the claimed SNP. The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities engaged in by scientists prior to applicants’ invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available. For example, the specification teaches the following:
[0041] The genotype of a SNP can be determined in a biological sample, by any suitable method. Many methods are available for detection of one or more alleles of a SNP, including sequencing methods, re-sequencing methods, amplification methods, and hybridization methods. Analysis of nucleic acids in a biological sample from an individual, whether amplified or not, may be performed using any of these methods. Exemplary methods include but are not limited to polymerase chain reaction (PCR), restriction fragment length polymorphism analysis (RFLP), reverse-transcription PCR (RT-PCR), isothermal amplification, 5′ fluorescence nuclease assay (e.g. TAQMAN assay), molecular beacon assays, heteroduplex mobility assays (HMA), single strand conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE). planar microarrays, bead arrays, sequencing, chemical cleavage of mismatch (CCM), and denaturing high performance liquid chromatography (DHPLC). One of ordinary skill in the art would understand that any known method of amplification of a nucleotide could be incorporated into a method to detect one or more alleles of a SNP. One of ordinary skill in the art would further understand that these methods of amplification of a nucleotide could use DNA, RNA, or a combination of the two
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112b
5. 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 6 and 9 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.
Claim 6 recites a “SNP within 1 million base pairs distance upstream or downstream from rs1883832 in strong linkage disequilibrium with rs1883832, wherein strong linkage disequilibrium is defined as coefficient of correlation (r) square (r2) value > 0.7”. This language is indefinite because a r2 value represents the statistical correlation between two polymorphic sites. The value of this correlation is entirely population dependent. The correlation between alleles of two polymorphic sites is not necessarily the same across populations. Therefore, although the recitation of >0.7 appears to be a fixed parameter by its representation in the claim as a numerical sentence, in reality, this is an entirely relative limitation. This illustrates a problem under 112b because it is unclear whether a variant that may have an “r2” value of 0.6 in one population but 0.8 in another population is within or outside the scope of the variants that can be used in the instant method claims, since the value of “r2” is dependent on which population is used to make the calculation. Thus, given this ambiguity, one skilled in the art cannot reasonably determine the metes and bounds of the claimed invention due to an inability to envision all members within the scope of the claims.
Claim 9 is rejected over the recitation of the phrase “the treatment that does not target CD40”. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not refer to a “treatment that does not target CD40”.
Claim Rejections - 35 USC § 112(a)
6. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
7. Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
A method of predicting if a subject will respond to Iscalimab for the treatment of Graves’ disease comprising:
genotyping CD40 SNPs rs1883832 and/or rs4810485 in a biological sample from a subject with Graves’ disease; and
predicting that the subject will respond to treatment with Iscalimab when the determined genotype of rs1883832 is homozygous for C or when the determined genotype of rs4810485 is homozygous for G, or
predicting that the subject will not respond to treatment with Iscalimab when the determined genotype of rs1883832 is heterozygous or homozygous for T or when the determined genotype of rs4810485 is heterozygous or homozygous for T.
does not reasonably provide enablement for the claims as broadly written. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
The claims are drawn to a method for predicting response of a subject to a CD40 targeted treatment. The claims do not define the CD40 targeted treatment in terms of its complete structure or any other relevant identifying characteristics. The claimed CD40 targeted treatment can be an antibody, protein, peptide, small molecule, an inhibitory RNA molecule (e.g., siRNA, shRNA, ribozymes, and antisense oligonucleotides), a vaccine, or a pharmaceutical. Thus, the claims broadly encompass a large genus of CD40 targeted treatments. Claim 7 states that the CD40-targeted active agent is an antagonistic anti-CD40 antibody. Claim 8 states that the antagonistic anti-CD40 antibody is BI 655064, ch5D12, bleselumab (ASKP 1240), Abbv-323 (ravagalimab), or iscalimab (CFZ533).
The claims recite a first step of genotyping CD40 SNPs rs1883832 and/or rs4810485 in a biological sample from a subject in need of immunosuppressant therapy. The claims broadly encompass subjects that are in need of immunosuppressant therapy for any reason. This genus broadly includes subjects needing immunosuppressant therapy for organ transplantation, stem cell/bone marrow transplantation, rheumatoid arthritis, lupus, Crohn’s disease, psoriasis, MDS, leukemia, lymphoma, asthma, sarcoidosis, etc.). Claim 3 states that the subject in need of immunosuppressant therapy is a patient with an autoimmune disease, a candidate for a transplant, or a recipient of a transplant. Claim 4 states that the subject in need of immunosuppressant therapy is a patient with an autoimmune disease and wherein the autoimmune disease is Graves' disease, antibody mediated autoimmune thyroid disease, Rheumatoid arthritis, Multiple Sclerosis (MS), Myasthenia Gravis, Sjogren's syndrome, Systemic Lupus Erythematosus, Crohn's disease, or a combination thereof.
The claims recite a step of predicting that the subject will respond to treatment with a CD40-targeted active agent when the determined genotype of rs1883832 is homozygous for C or when the determined genotype of rs4810485 is homozygous for G, OR predicting that the subject will not respond to treatment with a CD40-targeted active agent when the determined genotype of rs1883832 is heterozygous or homozygous for T or when the determined genotype of rs4810485 is heterozygous or homozygous for T.
Claim 6 further requires genotyping rs6074022, rs745307, rs11569309, rs3765457, rs112809897, a SNP within 1 million base pairs distance upstream or downstream from rs1883832 in strong linkage disequilibrium with rs1883832, wherein strong linkage disequilibrium is defined as coefficient of correlation (r) square (r2) value > 0.7, or a combination thereof in the biological sample. Whether or not two SNPs are in LD is dependent upon the population tested. Here no population is specified.
The nature of the invention requires a reliable correlation between rs1883832 and/or rs4810485 and responsiveness to a CD40 targeted therapy for the treatment of ANY disease or condition requiring immunosuppressant therapy. Further the claims require a reliable correlation between rs1883832 and SNPs linked to rs1883832 r2 <0.7 and responsiveness to CD40 targeted therapy.
Teachings in the Specification and Examples
The specification (Example 1, paras 0084-0087) teaches that blood samples were obtained from 13 patients with Graves' Disease that participated in a study of response to Iscalimab in treating Graves' disease. The blood samples were genotyped for 7 CD40 single nucleotide polymorphisms reported to be associated with Graves' Disease or other autoimmune diseases: rs6074022, rs1883832, rs745307, rs4810485, rs11569309, rs3765457, and rs112809897. Table 2 shows for each subject, the SNP genotyping results and the subject's response to treatment with iscalimab. The specification teaches that the inventors identified two single SNPs, rs1883832 and rs4810485, which each provided 100% positive predictive value for response to therapy with CD40-targeted monoclonal antibody (Iscalimab).
The specification (para 0090) further teaches that the 13 patients tested could be accurately categorized as non-responders or responders to the treatment based on the rs1883832 genotype alone, with responders homozygous for C at rs1883832 and non-responders heterozygous (C/T) at rs1883832. The homozygous T allele pair at rs1883832 occurs at relatively low frequency in the general population and was not present in any of these 13 patients. However, we anticipate that testing in a larger population will demonstrate that occurrence of homozygous T at rs1883832 is also predictive of non-response to the CD40-targeted antibody.
The specification (para 0091) teaches that similarly, the 13 patients tested could be accurately categorized as non-responders or responders to the treatment based on the rs4810485 genotype alone, with responders homozygous for G at rs4810485 and non-responders heterozygous (G/T) at rs4810485. The T allele is the minor allele at rs4810485 and the homozygous T allele pair at rs4810485 is not present in any of these patients. We anticipate that testing in a larger population will demonstrate that occurrence of homozygous T at rs4810485 is also predictive of non-response to the CD40-targeted antibody.
State of the Art and the Unpredictability of the Art
While the state of the art and level of skill in the art with regard to genotyping SNPs is high, the unpredictability in associating any particular SNP with a phenotype (such as responsiveness to CD40 targeted therapy) is even higher. The unpredictability is discussed below.
In the instant case, it is highly unpredictable if the correlations found between rs1883832 and rs4810485 and response to iscalimab for the treatment of Graves’ disease can be extrapolated to other types of CD40 targeted treatments for the treatment of the numerous other disease/conditions which require immunosuppressant therapy that are encompassed by the claims. Here it is relevant to note that the prior art of Visvanathan (Ann Rheum Dis 2019 78:754-760) conducted a pharmacogenomic study on the effects of BI 655064, an antagonistic anti-CD40 antibody in rheumatoid arthritis patients with rs4810485 SNP. Visvanathan teaches that the CD40 rs4810485 G/T polymorphism, which has previously been linked to RA disease, was genotyped in all 46 patients who provided informed consent: 21 patients were homozygous for GG, 18 patients were heterozygous for GT and 5 patients were homozygous for TT. T-allele carriers treated with BI 655064 showed a higher, but not statistically significant, ACR20 response (72.7% vs 50.0%; p=0.1558) and significantly higher ACR50 response (54.5% vs 16.7%; p=0.0403) vs placebo at week 12 (page 757, col 2). Thus, Visvanathan teaches that Rheumatoid arthritis patient with the T allele of rs4810485 are more like to respond to the CD40 targeted treatment, and this directly contradicts the instant claims which state that ALL patients needing immunosuppressant therapy are predicted to not respond to treatment with a CD40 targeted agent when they have one or two T alleles of rs4810485. The prior art demonstrates that rs4810485 may not be predictive of all CD40 targeted agents for the treatment of any disease or condition needing immunosuppressant therapy.
The specification (para 0054) implies that any SNP that is in strong linkage disequilibrium (r2 >0.7) with rs1883832 will also be predictive in the same way that rs1883832 is. However, this assertion is not supported by general statistical knowledge which accepts that correlations are not transitive. Sotos et al. teach that "unlike many common mathematical binary relations (e.g. equality, being greater than, divisibility), correlation is not transitive (p. 34; Sotos et al. Statistics Education Research Journal 2009, Nov. 8(2):33-55).” That is, just because A is correlated to B, and B is correlated to C, it does not necessarily follow that C is correlated to A. The only way to determine if C is correlated to A is to undertake a study and calculate the statistics to assess the relationship. This idea is supported by Terwilliger and Hiekkalinna who teach “there is precious little information about the correlation coefficient between X and Z, which can be gleaned from knowing the values of the correlation coefficients between markers X and Y, and that between markers Y and Z (p. 429; Terwilliger and Hiekkalinna European Journal of Human Genetics (2006) 14, 426–437. doi:10.1038/sj.ejhg.5201583; published online 15 February 2006)." Zill et al. (Molecular Psychiatry 2004 Vol 9 pages 1030-1036) exemplify this unpredictability when they teach a set of SNP where “Most of the SNPs were in tight and highly significant LD with each other (p. 1033 and Tables 3 and 4)”, yet only two of the highly linked SNP were found to be associated with major depression, even though the study would have had sufficient power to detect an effect if it were there (p. 1032, Table 2). It remains highly unpredictable whether or not a polymorphism that is in linkage disequilibrium with rs1883832 would be predictive of responsiveness to CD40 targeted therapy.
Because the claims encompass detecting a polymorphism that is in linkage disequilibrium with rs1883832, it is relevant to point out that there are expected to be numerous of polymorphisms that meet these structural requirements. However, the specification does not teach a predictable means for distinguishing between polymorphisms that meet these structural requirements and are associated with responsiveness to CD40 targeted therapy and polymorphisms that meet these structural requirements that are not associated with responsiveness to CD40 targeted therapy. Practice of the claimed invention using a polymorphism that is in linkage disequilibrium with rs1883832 requires knowledge that the polymorphism exists, knowledge that the polymorphism is associated with responsiveness to CD40 targeted therapy, and which allele is indicative of the phenotype. While it may have been known at the time of the invention how to identify a polymorphism that is in linkage disequilibrium with rs1883832, it was also known in the art that not every polymorphism in linkage disequilibrium with one another will be associated with the same phenotype. In other words not every polymorphism that is in linkage disequilibrium with rs1883832 will have the property of being correlated with responsiveness to CD40 targeted therapy.
Further the prior art teaches that the application of linkage disequilibrium findings is highly unpredictable. This unpredictability is highlighted by the teachings of Langdahl (Journal of Bone and Mineral Research 2000 Vol. 15, No. 3, pages 402-414). Langdahl teaches that linkage disequilibrium between alleles is population dependent and there can be considerable variation between the frequencies at which alleles are inherited. For example the reference cites that while one group reported that a repeat polymorphism in the IL-1RN gene was in linkage disequilibrium with the IL-1B (+3§54) polymorphism, Langdahl et al were unable to show linkage between these polymorphisms.
Additionally, Wall (Nature Reviews Genetics (2003) volume 4, pages 587-597) teaches that linkage disequilibrium (LD) refers to the fact that particular alleles at nearby sites can co-occur on the same haplotype more often than is expected by chance (page 587, 1st column, 1st paragraph). Wall teaches that patterns of LD are known to be noisy and unpredictable as pairs of sites tens of kilo bases apart might be in complete LD, whereas nearby sites from the same region can be in weak LD (page 587, 2nd column, last paragraph). Wall teaches that population history, population size, and population structure lead to differences in LD (page 588, 1st column, top). Wall teaches, “Measuring LD across a region is not straightforward" (box 1, last paragraph, page 588). Wall teaches it is difficult to compare results from different LD studies directly because of the variation in study design and methods of analyzing the data (page 591, 2nd column, 1st full paragraph). Wall teaches there are clear differences in LD between African’s and non-Africans (page 593, 1st column). Thus, Wall teaches that LD is not predictable.
As such both Langdahl and Wall demonstrate the unpredictability in associating a polymorphism that is in linkage disequilibrium with rs1883832 as a means for determining responsiveness to CD40 targeted therapy.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to predict the response of a subject to ANY CD40 targeted treatment for ANY disease or condition needing immunosuppressant therapy.
In order to practice the breadth of the claimed invention one of skill in the art would first have to recruit patients having a representative number of different diseases/conditions needing immunosuppressant therapy. Those patients would then need to be genotyped for rs1883832, rs4810485, as well as SNPs in LD with rs1883832 r2 <0.7. Then those patients would have to be treated with a representative number of different CD40 targeted treatments and followed overtime to see how the patients responded. Then all the data would need to be reviewed to determine if the claimed SNPs are predictive of response to all the CD40 targeted treatments in the patients having different disease/conditions that require immunosuppression. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a “predictable” factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the lack of guidance by the applicant and the particular examples, it is the conclusion that an undue amount of experimentation would be required to make and use the claimed invention in the full scope of the claims.
Written Description
8. Claims 1-7 and 9-10 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
A. The instant claims are drawn to a method of predicting response of a subject to a CD40 targeted treatment. The claims do not define the CD40 targeted treatment in terms of its complete structure or any other relevant identifying characteristics. The claimed CD40 targeted treatment can be an antibody, protein, peptide, small molecule, an inhibitory RNA molecule (e.g., siRNA, shRNA, ribozymes, and antisense oligonucleotides), a vaccine, or a pharmaceutical.
The specification teaches the following (numbering with respect to the PG-Pub)
[0021] The CD40-targeted active agent can be an antagonistic anti-CD40 antibody, or any other compound blocking CD40, preferably, a monoclonal antibody (mAb). Preferably the anti-CD40 antibody is a fully human or a humanized antibody. Antagonistic anti-CD40 mAbs block CD40/CD40L interaction to abrogate downstream signaling and suppress unwanted immune responses. Exemplary antagonistic anti-CD40 monoclonal antibodies include BI 655064, ch5D12, bleselumab (ASKP 1240), Abbv-323 (ravagalimab), and iscalimab (CFZ533).
The specification discloses a limited number of particular CD40 targeted therapies (namely BI 655064, ch5D12, bleselumab (ASKP 1240), Abbv-323 (ravagalimab), and iscalimab (CFZ533)). However, the disclosure of five different CD40 targeted therapies is insufficient to demonstrate possession of the genus as a whole. The breadth of the claims encompasses CD40 targeted therapies which the present inventors were not in the possession of, or which were not known to the inventors. The instant disclosure does not allow one of skill in the art to visualize or recognize the structure of additional CD40 targeted therapies that could be used to practice the claimed method. Therefore, the claims fail to meet the written description requirement because the claims encompass a significantly large genus of CD40 targeted therapies which are not adequately described in the specification.
B. Claim 6 recites detection of a “SNP within 1 million base pairs distance upstream or downstream from rs1883832 in strong linkage disequilibrium with rs1883832, wherein strong linkage disequilibrium is defined as coefficient of correlation (r) square (r2) value > 0.7”.
The claims broadly encompass the detection of SNPs in LD with rs1883832 having r2 values >0.7 that are predictive of response to treatment with CD40 targeted therapies. These SNPs have not been described in terms of their complete structure or any other relevant identifying characteristics. Whether or not two SNPs are in LD is dependent upon the population tested. Here no population is specified.
The specification teachings the following:
[0058] Linkage disequilibrium between two SNPs can be determined by any suitable method. Various software tools are available for determining LD, such as LDLink, an interactive suite of web-based tools developed to query germline variants in 1000 Genomes Project population groups of interest and generate interactive tables and plots of LD estimates, or LDLINKR, an R package designed to rapidly calculate statistics for large lists of variants and LD attributes that eliminates the time needed to perform repetitive requests from the web-based LDlink tool (Myers, T. A., et al. (2020) LDlinkR: An R Package for Rapidly Calculating Linkage Disequilibrium Statistics in Diverse Populations. Front. Genet. 11:157. doi:10.3389/fgene.2020.00157). Another available software tool is HAPLOVIEW, a comprehensive suite of tools for haplotype analysis for a wide variety of dataset sizes that generates marker quality statistics, LD information, haplotype blocks, population haplotype frequencies, and single marker association statistics (Barrett, J. C., et al. (2005) Haploview: analysis and visualization of LD and haplotype maps, Bioinformatics, 15 Jan. 2005, 21(2): 263-265, doi.org/10.1093/bioinformatics/bth457).
The specification teaches how to determine LD but does not teach any specific SNPs which meet the claim limitation of being within 1 million base pairs distance upstream or downstream from rs1883832 in strong LD with rs1883832, wherein strong LD is having a r2 value >0.7.
Regarding the genus of SNPs in strong LD with rs1883832 (r2 value >0.7) that are associated with response to CD40 targeted therapy, the specification provides no guidance as to how to determine from inspection if a SNP discovered to be in linkage disequilibrium with rs4813322 with a r2 value >0.7 is actually associated with response to CD40 targeted therapy. There is an implicit assertion in the suggestion to use SNPs in linkage disequilibrium with rs1883832 to “indirectly” detect the allele present at rs1883832, that all SNPs that are in strong linkage disequilibrium with rs1883832 would function in the claims since rs1883832 is predictive of the response to therapeutic CD40. However, this assertion is not supported by general statistical knowledge which accepts that correlations are not transitive (see previous discussion of Sotos et al. in this office action).
It remains highly unpredictable whether or not SNPs that are in linkage disequilibrium with rs1883832 are actually predictive of the response to therapeutic CD40 blockade. At the time the invention was made, it was typical to look to the publicly available HapMap database to identify SNPs in linkage disequilibrium with a main SNP. However, it is noted that the HapMap does not identify all SNPs. Rather, the HapMap lists particular currently known SNPs. The SNPs that are in linkage disequilibrium also vary with the different populations for which data is currently provided. These findings are supported by the teachings of Andiappan (BMC Genetics. 2010. 11: 36). Andiappan discloses that while the NCBI database lists over 26 million SNPs, the latest published HapMap provides data for only 3.1 million SNPs (p. 1, col. 2). Further, Andiappan genotyped 20 candidate genes on 5q31-33 and through re-sequencing identified 237 SNPs, of which only 95 (40%) were in Hapmap (see abstract). The reference also discloses that HapMaps are provided for 4 reference populations and there is variability between the data for the different populations (e.g., p. 2, col. 1). Andiappan cites Mueller as reporting that, in a study of European populations spanning sequence regions of 750Kb, only two out of the four studied populations were well represented in the HapMap CEPH population (p. 2, col. 1). Accordingly, the HapMap cannot be relied up to establish possession of SNPs that are in linkage disequilibrium with SNP rs1883832.
The specification provides evidence, that SNP rs1883832 is correlated with the response to CD40 targeted therapy. Examining SNP rs1883832, there is no common structural feature which would guide one attempting to practice the claimed invention in identifying other SNPs that would meet all of the requirements of the claimed methods. All members of the genus of markers useful in the claims have the same function, but no correlation between the naturally occurring allelic structures and their common properties is disclosed.
Additionally, the claims encompass the use of SNPs that are not disclosed in the specification but which meet the functional limitations in the claims. Discovering these species using routine methods in the prior art is not a practical way to describe the full extent of the claimed subgenus of methods because finding naturally occurring alleles could be successful only empirically. This is particularly true here where the naturally occurring alleles must be predictive of the response to CD4 targeted therapy. There is no description of the variant sites that exist in nature and there is no description of how the structure of rs1883832 relates to the structure of any other naturally occurring alleles. The general knowledge in the art concerning alleles does not provide any indication of how the structure of one allele is representative of unknown alleles, as are currently embraced by the claims.
The nature of alleles is that they are variant structures, and in the present state of the art, the structure of one allele does not provide guidance to the existence or structure of other alleles. In other words, the existence and structure of other alleles are not predictable from the species described. The description given is not adequate to allow one of skill in the art to distinguish members used in the methods of the claimed subgenus from other SNPs that are in linkage disequilibrium with rs1883832 that are not within the scope of the claimed methods because they are not predictive of the response to CD40 targeted therapy.
The instant specification does not provide sufficient written description to inform one of possession of the invention as a whole. The specification discloses that rs1883832 is predictive of the response to CD40 targeted therapy; however the claims are much broader because they also read on detection of SNPs that are in linkage disequilibrium with rs1883832. Therefore the claims encompass detecting a potentially enormous genus of nucleic acids. The written description issue applies to situations where the definition of the subject matter of the claims fails to provide description commensurate with the genus. Case law directly supports this rejection. As the District Court in University of Rochester v. G.D. Searle & Co., Inc. (2003 WL 759719 W.D.N.Y., 2003. March 5, 2003.) noted "In effect, then, the '850 patent claims a method that cannot be practiced until one discovers a compound that was not in the possession of, or known to, the inventors themselves. Putting the claimed method into practice awaited someone actually discovering a necessary component of the invention." This is similar to the current situation since the breadth of the current claims comprises the use of SNPs which the present inventors were not in the possession of, or which were not known to the inventors.
Since the specification does not disclose a representative number of SNPs in linkage disequilibrium with rs1883832 that are significantly predictive of a response to CD40 targeted therapy, one of skill would conclude that Applicants was not in possession of the claimed genus of methods which utilize polymorphisms in linkage disequilibrium with rs1883832 that have the required function of the SNPs to be used in the instant methods. One of skill in the art would conclude that applicant was not in possession of the claimed genus because a description of a particular SNP (rs1883832) is not representative of all SNPs in linkage disequilibrium with that SNP and is insufficient to support the claims.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682