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 .
Election/Restrictions
2. Applicant’s election without traverse of the species of the SNP of rs2516514, the EIM of ankylosing spondylitis, and the serological markers of the combination of anti-neutrophil cytoplasmic antibodies (ANCA), anti-saccharomyces cerevisiae antibodies (ASCA), anti-outer member porin C (anti-OmpC), and anti-bacterial flagellin (CBirl) in the reply filed on 04 September 2025 is acknowledged.
It is noted that in the reply, Applicant states that claims 63 and 69-70 read on the elected species of ankylosing spondylitis. However, claims 69 and 70 are limited to methods wherein the EIM is peripheral arthritis and peripheral arthritis is not identical to ankylosing spondylitis. While a symptom of ankylosing spondylitis can include peripheral arthritis, they are not the same conditions.
Claim Status
3. Claims 39, 51-56, 63, 69, 70, 73-78, and 81-84 are pending.
Claims 69 and 70 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 39, 51-56, 63, 73-78, and 81-84 read on the elected invention and have been examined herein to the extent that the claims read on the elected species of methods that determine or have determined that the subject has the SNP of rs2516514. It is noted that the claims encompass the non-elected species of SNPs other than the elected SNP of rs2516514 and combinations of SNPs. Claim 63 encompasses non-elected species of EIMs other than ankylosing spondylitis and claim 73 encompasses non-elected species of serological markers and combinations of markers. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Claim Interpretation
4. Claims 39, 51-52, 55-56, 63, 73-78, and 81-84 recite “A method for treating a subject having an inflammatory bowel disease, the method comprising administering to the subject a therapeutic agent, provided the subject has been determined to have a genotype comprising one or more single nucleotide polymorphisms selected from the group consisting of…rs2516514,”. The recitation of “provided the subject has been determined” is equivalent to reciting “if the subject has been determined.” Thereby, the claims do not necessarily require that an administering step is performed since the treating step is conditional - i.e., only occurs if the subject has been determined to have the SNP. With respect to the elected species, the claim recites that the administering step occurs if the subject is determined to have the SNP rs2516514. The specification discloses in Table 1 that 3 alleles exist at the polymorphic position in rs2516514 - i.e., the minor alleles of an A or a C and the major allele of a T:
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Thus, these claims encompass methods in which the administering step occurs if it has been determined that the subject has an A, C or T at the SNP rs2516514. Note that the claims do not require detecting any particular allele at the SNP.
Claims 53 and 54 recite “A method…. comprising determining whether the subject has a genotype comprising one or more single nucleotide polymorphisms selected from the group consisting of … rs2516514.” Thereby, with respect to the elected species, claims 53 and 54 encompass methods that determine if a subject has an A, C or T at rs2516514.
Claim Rejections - 35 USC § 101
5. 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 39, 51-56, 63, 73-78, and 81-84 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between a genotype of rs2516514 and risk of a subject developing an EIM, as well as the need to treat a subject. For instance, claims 39, 51-52, 55-56, 63, 73-78, and 81-84 recite “administering to the subject a therapeutic agent, provided the subject has been determined to have a genotype” of SNP rs2516514. Claims 53 and 54 recite “method for evaluating whether a subject having an inflammatory bowel disease will develop an extra-intestinal manifestation (EIM), the method comprising determining whether the subject has a genotype comprising” the SNP rs2516514. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
The claims require performing the step of “determining” the level of expression of one or more biomarkers. Neither the specification nor the claims set forth a limiting definition for "determining" and the claims do not set forth how “determining” is accomplished. The broadest reasonable interpretation of the determining step is that this step may be accomplished by reading information in a database or report to thereby ascertain the level of expression of the genes in a sample obtained from a subject. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
Claims 53, 54 and 84 require “determining” whether a subject has a genotype comprising a SNP at rs2516514. Neither the specification nor the claims set forth a limiting definition for "assaying" and the claims do not set forth how “determining” is accomplished. The claims do not specifically require performing an active laboratory process in which an allele at rs2516514 is detected in a nucleic acid sample from a subject. The broadest reasonable interpretation of the “determining” step is that this step may be accomplished by reading information in a database or report to thereby ascertain whether a subject has a genotype comprising a SNP rs2516514. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
Claims 53 and 54 also recite “evaluating” whether a subject having an IBD will develop an EIM. Neither the specification nor the claims set forth a limiting definition for “evaluating" and the claims do not set forth how “evaluating” is accomplished. As broadly recited, the “evaluating” step may also be accomplished by critical thinking processes and thus is an abstract step / process. “Evaluating” may also be accomplished verbally. Such verbal communication is also abstract, having no particular concrete or tangible form.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). To any extent that claims 53, 54 and 84, intend to encompass performing a laboratory assay to detect (an allele present at) SNP rs2516514, this step would be part of the data gathering process necessary to observe the judicial exception. This step does not practically apply the judicial exception.
Regarding claims 39 and 51, and the claims that depend therefrom, the administering step is conditional and only occurs if the subject is determined to have a genotype that comprises a SNP rs2516514 SNP. In view of the “provided the subject has been determined” language, the claims do not in fact require that the subject has been determined to have a genotype that comprises a SNP rs2516514. Thus, these claims encompass methods in which no administering step occurs. Additionally, claims 39, 51-52, 54-56, 63, 73-78, and 81-84 encompass methods wherein the subject is administered a therapeutic if any allele is present at rs2516514. There is no disclosure in the specification or prior art that a deletion occurs at rs2516514 and thereby all subjects would have some genotype at rs2516514. Accordingly, the administering step is not a practical application of the judicial exception since all subjects would be administered a therapeutic agent regardless of the allele determined to be present at rs2516514.
Additionally, claims 39, 51-52, 54-56, 63, 73-78, and 81-84 broadly recite administering any therapeutic agent to the subject. Administering any agent to any subject having any allele at rs2516514 to treat any condition does not constitute a practical application of the judicial exception. Rather, this is merely an “apply it” limitation.
Regarding specific treatments, see MPEP 2106.04(d)(2):
When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the following factors are relevant.
a. The Particularity Or Generality Of The Treatment Or Prophylaxis
The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application….
b. Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s)
The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). For example, consider a claim that recites a natural correlation (law of nature) between blood glucose levels over 250 mg/dl and the risk of developing ketoacidosis (a life-threatening medical condition). The claim also recites "treating a patient having a blood glucose level over 250 mg/dl with insulin". Insulin acts to lower blood glucose levels, and administering insulin to a patient will reduce the patient’s blood glucose level, thereby lowering the risk that the patient will develop ketoacidosis. Thus, in the context of this claim, the administration step is significantly related to the recited correlation between high blood glucose levels and the risk of ketoacidosis. Because insulin is also a "particular" treatment, this administration step integrates the law of nature into a practical application. Alternatively, consider a claim that recites the same law of nature and also recites "treating a patient having a blood glucose level over 250 mg/dl with aspirin." Aspirin is not known in the art as a treatment for ketoacidosis or diabetes, although some patients with diabetes may be on aspirin therapy for other medical reasons (e.g., to control pain or inflammation, or to prevent blood clots). In the context of this claim and the recited correlation between high blood glucose levels and the risk of ketoacidosis, administration of aspirin has at best a nominal connection to the law of nature, because aspirin does not treat or prevent ketoacidosis. This step therefore does not apply or use the exception in any meaningful way. Thus, this step of administering aspirin does not integrate the law of nature into a practical application.
Regarding claims 55 and 56, although many of the therapeutic agents administered are specific agents, the claims do not set forth what disorder, such as a particular EIM, that is being treated. Thereby, the administering step is not a practical application of the recited judicial exception. Moreover, several of the therapies are not specific. For example, claim 56 encompasses administering any steroid or administering vitamin A, D, E or K to the subject having IBD. However, administering a retinol (Vitamin A) cream to a subject or administering an anabolic-androgenic steroid is not known to treat the specific EIM elected of ankylosing spondylitis or a particular IBD.
Additionally, regarding claim 54, the additional step of administering may be performed at any point in the method. Thereby, claim 54 encompasses methods wherein the administering step occurs prior to determining whether the subject has a genotype comprising SNP rs2516514. In this instance, the administering step is also not a practical application of the judicial exception, but is merely extra-solution activity.
Accordingly, the very broadly recited step of administering a therapeutic agent to a subject having an IBD does not integrate the recited judicial exceptions into a practical application of the exceptions.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The claims do not require performing any specific, non-conventional transformative active process steps. Even if the claims did require active, laboratory steps (which they currently do not require) in which the genotype of the SNP is determined, methods of determining the nucleotide present at a SNP were well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification (e.g., para [0071]; para numbering herein is with respect to the published application).
See also MPEP 2106.05(d) II which states 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.
i. 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);
ii. 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);
iii. 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);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vii. 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); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting the genotype of a particular SNP, the identity of the SNP is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Improper Markush Grouping Rejection
6. Claims 39, 51-56, 63, 73-78, and 81-84 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush groupings of the SNPs of rs4349859, rs4463302, rs4418214, rs2069835, rs2516514, rs17030062, rs9305694, rs139009610, rs28732100, rs12199223, rs1265181, rs13417109, rs17026757, rs117670930, rs115994059, rs7297515, rs13166683, rs62376929, rs4418214, rs3819299, rs2373969, rs4151651, rs9366775, rs2858884, rs2858319, rs6917611, rs6930571, rs389419, rs76558762, rs7956721, rs887864, and rs9276424, and combinations thereof (recited in claim 39); and
rs61199332, rs7857730, rs497871, rs2516514, rs17030062, rs9305694, rs139009610, rs28732100, rs12199223, rs1265181, rs13417109, rs17026757, rs117670930, rs115994059, rs7297515, rs13166683, rs62376929, rs4418214, rs3819299, rs2373969, rs4151651, rs9366775, rs2858884, rs2858319, rs6917611, rs6930571, rs389419, rs76558762, rs7956721, rs887864, rs9276424, rs10056322, rs6461986, rs13421864, rs80079682, rs6905036, rs4349859, rs2842510, rs9276456, rs4463302, rs4418214, and rs2069835 and combinations thereof (claims 51-56, 63, 73-78, and 81-84)
are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 2117 states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 2117IIA).
Herein, the recited alternative species do not share a single structural similarity, as each polymorphism has a different chemical structure in that it consists of a different nucleotide alteration that occurs at a different location in the genome and each polymorphism is flanked by a unique nucleotide sequence. Thus, the polymorphisms do not share a single structural similarity. The only structural similarity present is that all of the polymorphisms involve nucleotides. The fact that the polymorphisms comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with risk of an extra-intestinal manifestation (EIM) in a subject having an inflammatory bowel disease (IBD) or the need to treat a patient having an IBD. For example, the polymorphism of an A, C or T at rs2516514 has a distinct chemical structure as compared to, for example, a polymorphism of a G or A at rs17030062 since the variant position can only be understood within the context of the surrounding nucleotides, which are structurally dissimilar, as shown below for these polymorphisms and flanking sequences set forth in present Table 1:
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Accordingly, while the different polymorphisms are asserted to have the property of being indicative of the risk of an EIM occurring in a subject having an IBD or the need to treat a subject having an IBD, they do not share a single structural similarity essential to this activity.
Further, the recited polymorphisms do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that all polymorphisms behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited polymorphisms possess the common property of being indicative of the risk of an EIM occurring in a subject having an IBD or the need to treat a subject having an IBD.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
7. 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 39, 51-56, 63, 73-78, and 81-84 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 39, 51-52, 55-56, 63, 73-78, and 81-84 are indefinite over the recitation of “administering to the subject a therapeutic agent, provided the subject has been determined to have a genotype.” The language of “provided the subject has been determined to have a genotype” indicates that the administering step only occurs in those instances in which the subject is determined to have the genotype. The claims include the possibility that the subject has not been determined to have the genotype. Thus, the claims include methods in which the administering step does not occur. It is unclear as to what step the claims do include if no administering step is performed and it is unclear as to how the claimed methods accomplish the objective set forth in the preamble of the claim of a “method for treating a subject having an inflammatory bowel disease.”
Claims 53 and 54 are indefinite and vague over the recitation that the method is one for “evaluating whether a subject having an inflammatory bowel disease will develop an extra-intestinal manifestation (EIM).” Claim 53 recites a single step of determining whether the subject has a genotype comprising the SNP rs2516514, and claim 54 recites an additional step of administering a therapeutic agent. The claims do not recite a nexus between determining whether the subject has a genotype comprising the SNP rs2516514 and evaluating whether a subject having an inflammatory bowel disease will develop an EIM. Thereby, it is unclear as to how the claims accomplish the objective set forth in the preamble of the claims of evaluating whether a subject having an inflammatory bowel disease will develop an EIM.
Claim Rejections - 35 USC § 112(a) - Enablement
8. 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.
Claims 39, 51-56, 63, 73-78, and 81-84 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
Claims 39, 51-52, 55-56, 63, 73-78, and 81-84 are drawn to a method for treating a subject having an inflammatory bowel disease (IBD), the method comprising administering to the subject a therapeutic agent, provided the subject has been determined to have a genotype comprising SNP rs2516514. Claims 53 and 54 are drawn to a method for evaluating whether a subject having an IBD will develop an extra-intestinal manifestation (EIM), the method comprising determining whether the subject has a genotype comprising SNP rs2516514.
The specification discloses in Table 1 that 3 alleles exist at the polymorphic position in rs2516514 - i.e., the minor alleles of an A or a C and the major allele of a T:
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Thus, when read in light of the specification, it appears that the claims encompass methods that administer a therapeutic agent to a subject having IBD if the subject has been determined to have an A, C or T at the polymorphic position of rs2516514; and methods for evaluating whether a subject having IBD will develop an EIM based on determining whether the subject has an A, C or T at the polymorphic position of rs2516514.
However, the specification teaches in Table 10D that the “Effect Allele” for rs251651 is a “G” allele, with respect to an association with the EIM of ankylosing spondylitis (AS) . It is also disclosed that the minor allele frequency (MAF) - i.e., for an A or C allele, as defined in Table 1, is 21.39%.
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It is also disclosed in Embodiment 48: “48. The method of any of embodiments 29-47, wherein the genotype comprises a polymorphism selected from the group consisting of a “A”, or “T” allele at rs2516514 (SEQ ID NO:2001).” Wherein Embodiment 29 recites (in part): “29. A method of treating an inflammatory, fibrostenotic, and fibrotic, disease or condition in a subject comprising.”
It is thereby unclear as to which allele at rs2516514 is considered to be the allele indicative of a subject having IBD developing an EIM, and particularly the EIM of AS. If the “G” allele recited in Table 10D is intended to refer to the allele on the second strand of the DNA, the result would also be confusing because both the C and A alleles (or G and T alleles on the second strand) are considered to be the minor allele, and Table 10D lists the “MAF” as a whole as 21.39%.
Accordingly, to the extent that the claims are intended to encompass methods wherein the subject is administered the therapeutic agent (or evaluated to be at risk of developing an EIM) based on the presence of a particular allele/genotype at rs2516514, the specification does not provide sufficient guidance as to how to practice the claimed methods because the specification does not clearly identify which allele at rs2516514 is considered to be the allele indicative of the risk of the subject having IBD developing an EIM.
To the extent that the claims are intended to encompass methods wherein the subject is administered the therapeutic agent based on the presence of any one of an A, C, T or G at rs2516514, the specification has not enabled such methods because the specification does not provide sufficient guidance as to what therapeutic treatment is administered to the subjects following the detection of any one of an A, C, T or G at rs2516514. That is, for subjects who do not have a risk allele at rs2516541, insufficient guidance is provided as to the identity of the therapeutic agent that is administered to the subject when it is unclear as to what condition the subject is to be treated. Note that the claims encompass in general a method of treating a subject having IBD, but do not state the condition that is treated (e.g., do not require treating IBD or an EIM).
Secondly, the claims encompass methods wherein the EIM is any extra-intestinal disorder or any one of the disorders recited in claim 63: i.e., “i)ankylosing spondylitis, sacroiliitis, erythema nodosum, pyoderma, gangrenosum, psoriasis, a manifestation in the eve, primary sclerosing cholangitis, or peripheral arthritis, or a combination thereof;(ii) ankylosing spondylitis, sacroiliitis, or both ankylosing spondylitis and sacroiliitis:(iii) erythema nodosum, pyoderma, gangrenosum, psoriasis, or a combination thereof,(iv) manifestation in the eve:(v) primary sclerosing cholangitis:(vi) peripheral arthritis: or(vii) ankylosing spondylitis, sacroiliitis, erythema nodosum, pyoderma gangrenosum, psoriasis, a manifestation in the eye, or primary sclerosing cholangitis, or a combination thereof.”
However, the specification appears to teach only that a G allele at rs2516514 was present at an increased frequency in UC and CD subjects having the phenotype of AS. The specification does not teach that an allele at the rs2516514 SNP is correlated with a representative number of other extra-intestinal manifestations.
A functional effect for a risk allele at rs2516514 is not disclosed in the specification. At Table 1, the specification does not list a particular gene in which the rs2516514 SNP is located, and Table 10D lists the “candidate genes” of HCG26 and MICB, but does not provide a particular location for this SNP in these genes or an encoded protein. GWAS teaches that rs2516514 is present in the HCP5 gene and is an intron variant (see GWAS Catalog for rs2516514, available via url: < ebi.ac.uk/gwas/variants/rs2516514>, printed on 24 September 2025).
In the absence of a showing of a correlation between a risk allele at rs2516514 and the development of a representative number of distinct EIMs in subjects having IBD and the absence of any type of functional effect of a risk allele at rs2516514, it is highly unpredictable as to whether the results set forth in the specification for the EIM of AS can be extrapolated to a representative number of distinct EIMs.
Thirdly, the elected species of a serological marker for claim 73 is the combination of anti-neutrophil cytoplasmic antibodies (ANCA), anti-saccharomyces cerevisiae antibodies (ASCA), anti-outer member porin C (anti-OmpC), and anti-bacterial flagellin (CBirl). However, the specification does not teach individual subjects having each of these markers. Rather, the specification teaches distinct subjects having different EIMs that have one or more (but not all) of these markers (see, e.g., Tables 9A and 9B). For instance, in Table 9A, it is disclosed that CD subjects having the AS phenotype had the serological marker of CBir1_pos.
Lastly, the claims encompass methods wherein the subject may be a non-human mammalian subject. Note that the specification states that “[0611] The terms “subject” encompass mammals. Non-limiting examples of mammal include, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.” However, all results provided in the specification are limited to human subjects. The specification does not teach the existence of the rs2516514 polymorphism in a representative number of non-human species. Even if it is established that the rs2516514 polymorphism exists in other organisms, the specification does not teach an association between a particular allele of this polymorphism and risk of an EIM in subjects having an IBD in a representative number of non-human species. It is thereby unpredictable as to whether the rs2516514 SNP occurs in a representative number of non-human species and is correlated with the development of an EIM, and particularly AS, in a representative number of non-human species.
While methods for sequencing nucleic acids are known in the art, such methods provide only the general guidelines that allow researchers to study the frequency of particular alleles at polymorphic sites in different populations. The results of performing such methodology are highly unpredictable. The specification has provided only an invitation to experiment. The specification does not provide a predictable means for practicing the broadly claimed invention so as to ascertain whether an allele / genotype at rs2516514 is correlated with the development of a representative number of EIMs in human subjects having an IBD in human subjects and in a representative number of non-human subjects.
As set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention. Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
Case law has established that '(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.'" In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that '(t)he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art". The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genetech Inc. v Novo Nordisk 42 USPQ2d 1001 held that '(I)t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement".
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Priority
8. The present claims are entitled to the filing date of PCT/US2020/062404, filed 25 November 202. It is noted that a claim as a whole is assigned an effective filing date rather than the subject matter within a claim being assigned individual effective filing dates. U.S. provisional application 62/941,209, filed 27 November 2019 does not provide support for each of the embodiments in independent claims 39, 51 and 53 and each of the embodiments in the dependent claim. For example, the ‘209 application does not teach a method of treating a subject having an IBC comprising administering to the subject a therapeutic agent provided the subject has been determined to have a genotype comprising a SNP at rs2516514 or a method for evaluating whether a subject having an inflammatory bowel disease will develop an extra-intestinal manifestation (EIM) comprising determining whether the subject has a genotype comprising a SNP at rs2516514.
If Applicant asserts that the present claims are entitled to priority to the provisional application, Applicant should point to specific teachings (e.g., by page and line number) in the priority applications to establish priority for each of the recitations set forth in the claims.
See MPEP 2163 II at “(b) New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, 365, or 386” states “To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure.”
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
The prior art of Khrom et al (Gastroenterology, “MEGA-ANALYSIS REVEALS NOVEL GENETIC ASSOCIATIONS WITH EXTRAINTESTINAL MANIFESTATIONS IN IBD”. 158(6) Suppl 1, pp. S157, published May 2020, meeting held January 23-25, 2020; available via url: < gastrojournal.org/article/S0016-5085(20)31079-9/pdf>; cited in the IDS) teaches analyzing genotype data obtained using an ImmunoChip array to identify genetic associations with EIMs in Caucasian subjects having IBDs. Khrom reports:
“We identified EIM associations at established IBD susceptibility loci, as well as putative novel loci. Known IBD locus HLA-B reached genomewide (GW) significance for EIM-4 and also AS (rs6905036 PEIM4=2.9E-08 OREIM4=1.7;PAS=
1.1E-17 ORAS=2.8). GW association was also observed at MICA/HCP5 with EIM-4 and also AS (rs2844510 PEIM4=1.9E-08 OREIM4=1.6;PAS=1.8E-15 ORAS=2.5) and reached suggestive significance with UVIR (PUVIR=4.0E-06 ORUVIR=2.0). Novel associations include GW significance with METTL24 (rs7745186 PAS=1.2E-08 ORAS=0.54) and CACNA1C (rs11614966 PAS=1.7E-09 ORAS=0.40) with AS; as well as PLD5 with EN and suggestive significance with EIM-4 (rs12757496 PEN=4.5E-08 OREN=0.26;PEIM4=5.7E-07 OREIM4= 0.49). Analyses of imputed HLA alleles demonstrated association with AS at known alleles HLA-B*27 (P=9.0E-09 OR=2.7) and HLA-C*02 (P=2.8E-04 OR=2.0), and psoriasis at HLA-C*06 (P=6.3E-04 OR=1.5). Putative novel association was identified for psoriasis at HLA-DPB1*10 (P=3.4E05 OR=2.8) and HLA-DPB1*14 (P=5.3E-04 OR=2.0).”
However, Khrom does not specifically teach that the methods disclosed therein evaluated rs2516514 to determine an association between a genotype at rs2516514 and the risk of developing an EIM in a subject having an IBD. Nor does Khrom teach or suggest methods of treating a subject having an IBD comprising administering a therapeutic agent to the subject provided the subject has been determined to have a genotype at rs2516514.
Yang et al (CN104293969A; 21 January 2015; translation included at end of document) discloses methods of detecting a SNP at chr6:31446930 in the region of 6p21.3, having an A or C allele (p. 3 of the translation). It is disclosed that human subjects having an A allele at this SNP have an increased susceptibility to ankylosing spondylitis (AS), whereas subjects having a CC genotype have the lowest susceptibility to AS (e.g., p. 3 of the translation). Yang does not provide an rs number for the SNP or a reference genome to define the nucleotide position for the SNP on chromosome 6. Note that the GWAS Catalog for rs2516514 (cited above) teaches that the rs2516514 SNP is located in the region of 6p21.33 at position 31,479,358, with respect to GRCh38. NCBI Database (Variation Viewer for rs2516514, available via url: < ncbi.nlm.nih.gov/variation/view/?assm=GCF_000001405.40>, printed on 24 September 2025) teaches that rs2516514 is located at position chr6:31447135, with respect to GRCh37. Yang et al does not teach or suggest the presently claimed methods and particularly does not teach that the subjects screened therein for the SNP at chr6:31446930 have an IBD.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682