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 with traverse of the species of the chromosome interaction probe of “Hg38_2_151357305_151361853_151612320_161619007_RF” (i.e., “the first marker listed in Table 1A”), and specifically the probe of SEQ ID NO: 1 and the primers of SEQ ID NOs: 51 and 52, in the reply filed on 05 January 2026 is acknowledged. The traversal is on the ground(s) that:
“Claim 1 is a unified generic invention because it was not known in the art how to detect the muscular atrophy status of an individual by determining the presence or absence of a muscular atrophy related chromosome interaction represented by the probes shown in Table 1 as required by claim 1. Indeed, Lim et al. fails to provide any teaching of any specific muscular atrophy related chromosome interactions or of any specific probes with which to identify the muscular atrophy related chromosome interactions. The Examiner has not pointed to evidence in Lim et al. or elsewhere in the prior art that provides the necessary knowledge of specific muscular atrophy related chromosome interactions of claim 1. In contrast, the instant application and Claim 1 as amended require specific muscular atrophy related chromosome interactions and provides the probes to identify muscular atrophy related chromosome interactions (i.e., probes of Table 1). Accordingly, Claim 1 provides a generic method with inventive step over the known art. Lim et al document has very limited teaching in respect of use of chromosome interactions..”
This is not found persuasive because Lim et al was cited to establish that the linking technical feature of methods for detecting a chromosome interaction were known in the priori art and thus this technical feature does not constitute a special technical feature. It is maintained that Lim et al provides sufficient direction and guidance to practice the linking technical feature of methods of detecting a chromosome interaction, including methods of performing EpiSwitch or 3C to detect the chromosome interaction. Note also that the disease detected by Lim of Amyotrophic Lateral Sclerosis (ALS) is a progressive disease that causes muscular atrophy and thereby is a “muscular atrophy related” disorder. See also Akoulitchev et al (WO 2019069067; discussed in detail below) which teaches methods for detecting Huntington’s disease (which encompasses a muscular atrophy disease) or Amyotrophic Lateral Sclerosis (ALS) by detecting a chromosome interaction (see Tables 1 and 12 and p. 2 line 7 to p. 3, line 8). Akoulitchev also establishes that the linking technical feature of methods of detecting a chromosome interaction, particularly to detect a muscular atrophy status, using probes was known in the prior art and thereby is not a special technical feature.
Further, claim 1 is not a generic method, as asserted by Applicant. Rather, claim 1 requires detecting specific, distinct chromosomal interactions. The species also lack unity because the species comprise different chromosomal interactions each involving different genes/loci and different nucleotide sequences. Thereby, each chromosomal interaction has a different chemical structure. Each of the genes / loci / probes occur at different locations in the genome and have different biological activities and effects. Thus, there is no special technical feature linking the recited groups of chromosomal interactions as is required to establish unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
It is noted that the response states that “The chromosome interaction is present on chromosome 2 and is formed by chromosome positions numbers 151357307 to 151357336 interacting with chromosome position numbers 151618976 to 151619005.” However, in view of teachings in Table 1A and Applicant’s election of the first chromosome interaction in Table 1A, the final chromosome position number should be 151619007.
Claim Status
3. Claims 1-11 are pending.
Claim 2 and 9 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 1, 3-8, 10 and 11 read on the elected invention and have been examined herein to the extent that the claims read on the elected species. The claims encompass non-elected chromosome interactions, probes and primers. Prior to the allowance of the 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.
Specification
4. The use of the terms EpiSwitch™, HEX™, TEXAS RED® and FAM™, which are a trade name or a mark used in commerce, have been noted in this application. The specification should be reviewed for any additional trademarks or trade names. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
5. Claims 3-8 and 10 are objected to because of the following informalities:
Claims 3-8 and 10 are objected to because these dependent claims improperly utilize the article “A” in referring to the prior claim - e.g., “A method according to claim 1”). The preamble of claims 3-8 and 10 should be amended to recite the article “The” (e.g., “The method according to claim 1...”).
Appropriate correction is required.
Improper Markush Grouping Rejection
6. Claims 1, 3-8 , 10 and 11 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 § 706.03(y).
The Markush groupings of the chromosome interactions represented by a probe in Table 1, and the probes and primers of Table 1 used to detect the chromosome interactions (see claim 6), and combinations thereof 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 706.03(y) 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 706.03(y)IIA).
Herein, the recited alternative species do not share a single structural similarity, as each chromosome interaction occurs at a different location in the genome and involves different nucleotide sequences. Thus, each chromosome interaction has a different chemical structure in that it consists of a different nucleotide sequence. The probes and primers used to detect the chromosome interactions also have a different chemical structure in that they consist of different nucleotide sequences. The only structural similarity present is that all of the chromosome interactions (and probes and primers) comprise nucleotides. The fact that the chromosome interactions comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides alone is not essential to the asserted common activity of being correlated with muscular atrophy. Accordingly, while the different chromosome interactions are asserted to have the property of being “muscular atrophy related,” they do not share a substantial structural similarity essential to this activity.
Further, the recited chromosome interactions do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that the chromosome interactions 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 chromosome interactions possess the common property of being indicative of muscular atrophy status. Nor is there any evidence of record to establish that it is clear from their very nature that the recited probes and primers possess the common property of being useful to detecting a chromosome interaction indicative of muscular atrophy status.
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 § 101
7. 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, 3-8, 10 and 11 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 the presence of a chromosome interaction “represented by” the “Hg38_2_151357305_151361853_151612320_161619007_RF” probe and specifically the probe of SEQ ID NO: 1 and muscular atrophy. In particular, the claims recite detecting muscular atrophy by determining the presence or absence of a muscular atrophy related chromosome interaction represented by the probe of “Hg38_2_151357305_151361853_151612320_161619007_RF.” 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).”
Claims 1, 3, 5, 7, 8 and 11 require performing the step of “determining” whether a chromosome interaction is present or absent. 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 whether the chromosome interaction is present or absent. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea. Note that the claims do not require performing a nucleic acid detection assay on a nucleic acid sample obtained from a subject to detect the presence or absence of the chromosome interaction in the nucleic acid sample. While claim 3 recites that one of the options includes determining the chromosome interaction in a sample, the claim is not limited to this option.
Claim 7 recites that the method is one that diagnosis or determines the prognosis for muscular atrophy. As broadly recited, the claim encompasses mentally diagnosing or determining a prognosis and thereby encompasses an abstract step / process. The diagnosing or determining a prognosis may also be accomplished verbally. Such verbal communication is also abstract, having no particular concrete or tangible form.
Similarly, claim 8 recites that the method is one that is carried out to select an individual for a medical treatment. In the absence of a clear definition in the specification for what is encompassed by the selecting and in the absence of any limitation in the claim as to how the selecting is accomplished, selecting an individual for medical treatment is considered to be an abstract step / process since as broadly recited this step can be performed mentally or verbally.
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). The additionally recited non-patent-ineligible steps in the claims, and particularly in claims 4, 6 and 10, are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Claim 11 recites a method of performing the method of claim 1 and administering an anti-muscular atrophy therapeutic to an individual that has been identified as having muscular atrophy by the method of claim 1. However, claim 1 encompasses methods which detect the absence of the chromosome interaction and thereby methods in which the subject is not identified as having muscular atrophy. Accordingly, as broadly recited, claim 11 need not include an administering step in those instances in which claim 1 is performed and the absence of the chromosome interaction and thereby absence of muscular atrophy is detected.
Further, the treating step in claim 1 is recited at a high degree of generality, covering any type of treatment that could be considered an “anti-muscular atrophy” therapeutic agent. Note that he specification does not provide a limiting definition for what constitutes an “anti-muscular atrophy therapeutic agent.” As generically recited, the administering step constitutes no more than an “apply it” limitation – i.e., general instructions to a doctor to apply the judicial exception. Accordingly, the administering step in claim 11 does not integrate the judicial exception so as to practically apply the judicial exception.
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 claim 7 and the recitation that the method “the method is carried out to select an individual for receiving therapy or a treatment for muscular atrophy,” as discussed above, “selecting” an individual for a medical treatment is an abstract / non-patent-eligible step is not a practical application of the judicial exception.
Applicant’s attention is directed to MPEP 2106.04(d)(2):
Examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. An example of such a limitation is a step of "administering amazonic acid to a patient" or a step of "administering a course of plasmapheresis to a patient." If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. For example, a step of "prescribing a topical steroid to a patient with eczema" is not a positive limitation because it does not require that the steroid actually be used by or on the patient, and a recitation that a claimed product is a "pharmaceutical composition" or that a "feed dispenser is operable to dispense a mineral supplement" are not affirmative limitations because they are merely indicating how the claimed invention might be used.
Similarly, herein, “selecting” an individual for treatment is not equivalent to administering a treatment to an individual and is not a practical application of the judicial exception.
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. As discussed above, the majority of the claims recite only non-patent-eligible steps since these steps may be performed mentally and are the judicial exception of an abstract idea..
Note that claims 3, 5 and 6 encompass methods which require only the additional limitation that the presence or absence of the chromosome interaction is detected in a sample. To the extent that claim 6 encompasses the option of methods in which the presence or absence of the chromosome interaction is detected using a probe having 70% identity to a probe sequence in Table 1, as broadly recited, this claim encompasses using any Hg38_2_151357305_151361853_151612320_161619007_RF” probe. This is not a specific probe and thereby does not add an inventive concept to the recited judicial exceptions. The claim also encompasses using a probe that has 70% identity to a probe or primer “shown in Table 1.” This language is broad covering any probe having 70% identity to a portion of the sequence recited for the elected probe of SEQ ID NO: 1 and any primer pair having 70% identity to a portion of the sequence of the elected primer pair of SEQ ID NO: 51 or 52. Claim 6 is not limited to methods that require using a probe comprising SEQ ID NO: 1 or a primer pair comprising SEQ ID NO: 51 and SEQ ID NO: 52 to detect the presence or absence of a chromosome interaction in a nucleic acid sample from the individual, so as to add something significantly more to the recited judicial exceptions.
Regarding claims 4 and 10, the steps recited in these claims were well-known, routine and conventional in the prior art.
See, for example, De Laat et al (U.S. 2010/0075861) which teaches a method comprising:
Claim 1. A method for analyzing the frequency of interaction of a target nucleotide sequence with one or more nucleotide sequences of interest (e.g. one or more genomic loci) comprising the steps of: (a) providing a sample of cross-linked DNA; (b) digesting the cross-linked DNA with a primary restriction enzyme; (c) ligating the cross-linked nucleotide sequences; (d) reversing the cross linking; (e) digesting the nucleotide sequences with a secondary restriction enzyme; (f) ligating one or more DNA sequences of known nucleotide composition to the available secondary restriction enzyme digestion site(s) that flank the one or more nucleotide sequences of interest; (g) amplifying the one or more nucleotide sequences of interest using at least two oligonucleotide primers, wherein each primer hybridises to the DNA sequences that flank the nucleotide sequences of interest; (h) hybridising the amplified sequence(s) to an array; and (i) determining the frequency of interaction between the DNA sequences.
De Laat further teaches labeling probes with art-recognized conventional fluorescent labels (para [0252-0254]) and probes that may be 25 nucleotides in length (and thereby between 10-40 nucleotides; see para [0279]).
The finding that the EpiSwitchTM and 3C technology were well-known and conventional in the prior art is further evidenced by the teachings of Ramadass (WO 2016/207647), Lim et al (J. Neurological Sciences. 2017. 381: 616, Abstract 1706; cited in the restriction requirement of 11/05/2025), Jakub et al (Melanoma Research. 2015. 25: 408-411), and Stadhouders et al (Nature Protocols. 2013. 8(3): 509-524).
Further, the review article of Crutchley et al (Biomarkers in Medicine. 2010. 4(4): 611-629) discusses the well-known techniques of 3C, 4C and 5C, which include performing qPCR with primers and probes.
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);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
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.
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.
Claim Rejections - 35 USC § 112(b) - Indefinite
8. 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 1, 3-8, 10 and 11 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.
A. Claims 1, 3-8, 10 and 11 are indefinite over the recitation of “the probes shown in Table 1” (claim 1), “the probes shown in Table 1” (claim 6) and “the primer pairs shown in Table 1” (claim 6). MPEP 2173.05(s) states:
“Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
Herein, the reference to the probes and primers of Table 1 renders the claims incomplete.
B. Claims 1, 3-8, 10 and 11 are indefinite over the recitation of “chromosome interactions represented by the probes shown in Table 1” because this phrase is not clearly defined in the specification or the claims and there is no art recognized definition for this phrase. It is unclear as to how a chromosome interaction is “represented by” a probe. The language of “represented by” does not make clear the relationship between the chromosome interaction and the probe. It is also unclear as to what “probe” in table 1 is being referred to. With respect to the elected species Table 1A recites a “probe” of “Hg38_2_151357305_151361853_151612320_161619007_RF.” However, this is actually described in the specification as a chromosome interaction and not a probe per se. The response to the restriction / election requirement of 01/05/2026 also refers to this as a chromosome interaction stating “Applicants elect with traverse the single chromosome interaction which is listed first in table 1A that is designated “Hg38_2_151357305_151361853_151612320_151619007_RF.” Table 1 beginning at p. 34 also recites a “Probe sequence” consisting of SEQ ID NO: 1, with respect to the elected species. To the extent that the probe is intended to be “Hg38_2_151357305_151361853_151612320_151619007_RF” it is unclear as to what constitutes this probe. For example, it is unclear as to whether this probe comprises the sequences of each of 151357305 to 151361853 and 151612320 to 151619007 of chromosome 2, as defined in Hg38 and/or if the probe comprises only the sequences of chr2: 151357305-151361853 with respect to Hg38 and/or only the sequences of chr2: 151612320-151619007, respect to Hg38.
C. Claims 3, 5 and 6 are indefinite over the recitation of “said typing” (see claim 3) because this phrase lacks proper antecedent basis since the claim does not previously refer to typing.
D. Claims 3, 5 and 6 are indefinite over the recitation of “two regions each corresponding to the regions of the chromosome which come together in the chromosome interaction because in the context of the claim, it is unclear as what is encompassed by “corresponding.” For instance, it is unclear as to whether the claims require that the two regions are the regions that come together in the chromosome interaction or if they two regions may be nearby or distal regions or if the two regions may be any two regions having an unspecified level of sequence identity with regions that come together in a chromosome interaction.
E. Claims 5 and 6 are indefinite over the recitation of “said ligated DNA.” While claim 3, from which claims 5 and 6 depend, recites “ligated nucleic acid,” the claims do not previously recite “ligated DNA.”
F. Claim 7 is indefinite and vague. The claim states that the method is carried out to select an individual for receiving therapy or treatment or to diagnose or prognose muscular atrophy. However, the claim omits any steps that are performed to accomplish the objectives of selecting an individual to receive therapy or treatment or for diagnosing or determining the prognosis of muscular atrophy. The claim does not set forth how detecting the presence or absence of the chromosome interaction per se results in the selection of an individual for therapy or treatment or results in the diagnosis or the prognosis of muscular atrophy
G. Regarding claims 7 and 8, the phrase "preferably" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
H. Claim 10 is indefinite over the recitation of “said probe” because it is not clear as to whether this refers to the “probe which binds the ligation site during the PCR reaction” or “the probes shown in Table 1” recited in claim 1, from which claim 10 depends.
I. Regarding claim 10, each of the recitations of the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
J. Claim 10 contains the trademark/trade names of HEX™, TEXAS RED® and FAM™. That is claim 10 recites “said fluorophore is selected from HEX, Texas Red and FAM.”MPEP 2173.05 states “If the trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982).”The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present claim, the trademark/trade name is used to identify/describe a particular type of fluorophore and, accordingly, the identification/description is indefinite.
K. Claim 11 is indefinite. Claim 11 requires performing the method of claim 1 which encompasses detecting the presence or absence of the chromosome interaction. Yet, claim 11 also recites “an individual that has been identified as having muscular atrophy by the method of claim 1.” Since claim 11 does not require performing the method of claim 1 and detecting the presence of the chromosome interaction, it is unclear as to how the recitation of “an individual that has been identified as having muscular atrophy by the method of claim 1” relates to the remainder of the claim. It is also unclear as to whether “an individual that has been identified” is the same as or distinct from “an individual” on which the method of claim 1 is carried out. Additionally, it is unclear as to what is meant by “carrying out the method of claim 1 on an individual” per se. While it is clear as to what is meant by “carrying out the method of claim 1” on a nucleic acid sample obtained from an individual, it is unclear as to how the recited method is carried out “on” an individual.
Claim Rejections - 35 USC § 112(a) – Written Description
9. 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 1, 3-8, 10 and 11 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 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 or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description rejection.
In analyzing the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note that with regard to genus/species situations, a “Satisfactory disclosure of a “representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.”
The claims are drawn to methods of detecting the muscular atrophy status of an individual comprising determining the presence or absence of “muscular atrophy related chromosome interaction represented by the probes shown in Table 1. In the response of 05 January 2026, Applicant elected the “chromosome interaction” of “Hg38_2_151357305_151361853_151612320_161619007_RF.” However, Table 1A lists “Hg38_2_151357305_151361853_151612320_161619007_RF” as a probe. The response also elected the probe of SEQ ID NO: 1 and the primer pair of SEQ ID NO: 50 and 51. Claim 6 encompasses methods that detect a chromosome interaction with a probe having at least 70% identity to a probe “shown in “ Table 1, which thereby includes, with respect to the elected species, methods using probes having 70% identity to the full length sequence of SEQ ID NO: 1 and probes comprising a sequence having 70% identity to a fragment of SEQ ID NO: 1. Claim 6 also encompasses methods that detect a chromosome interaction with a primer having at least 70% identity to a primer pair “shown in “ Table 1, which thereby includes, with respect to the elected species, methods using primer pairs having 70% identity to the full length sequence of SEQ ID NO: 51 and 52 and primer pairs comprising a sequence having 70% identity to a fragment of SEQ ID NO: 51 and 52.
Claim 7 recites that the method is one carried out to select an individual for receiving therapy or a treatment for muscular atrophy, and/or the method is carried out to diagnose muscular atrophy or to determine prognosis for muscular atrophy, and preferably to determine severity of muscular atrophy. Claim 11 recites that the method is one that identifies an individual in need of a therapeutic agent for muscular atrophy.
In view of the broad language recited in the claims, including the language that the chromosome interaction is “represented by” the probe of “Hg38_2_151357305_151361853_151612320_161619007_RF,” the claims do not define the chromosomal interaction in terms of specific structural attributes or any other relevant identifying characteristics. The claims include interactions that may be hybridization interactions, translocation interactions, methylation interactions, and interactions that are, or which occur as a result of a mutation or polymorphism, and/or interactions in which one region of a chromosome affects another region of a chromosome, e.g., by affecting transcription or methylation events..
The specification (para [0032]; note that paragraph numbering herein is with respect to the published application) states that:
“The chromosome interactions which are typed in the invention are typically interactions between distal regions of a chromosome, said interactions being dynamic and altering, forming or breaking depending upon the state of the region of the chromosome” (emphasis added).
This disclosure does not provide a limiting definition for “chromosome interactions.” Rather, this disclosure describes in general examples of different types of interactions that can occur between distal regions of a chromosome.
The specification goes on to state:
‘[0190] The EpiSwitch™ platform technology detects epigenetic regulatory signatures of regulatory changes between normal and abnormal conditions at loci. The EpiSwitch™ platform identifies and monitors the fundamental epigenetic level of gene regulation associated with regulatory high order structures of human chromosomes also known as chromosome conformation signatures.”
Thus, the specification generally describes an interaction wherein distal regions of a chromosome are juxtaposed to one another along the length of the chromosome and this interaction between the juxtaposed regions is detected using the EpiSwitchTM platform.
However, the claims encompass a significantly large genus of chromosome interactions “represented by” the probe of ““Hg38_2_151357305_151361853_151612320_161619007_RF” – i.e., any type of an interaction between chromosomal sequences that include positions 151357305 to 151361853 with positions 151612320 to 161619007 of chromosome 2 (chromosome positions are with respect to Hg38), or nearby or related sequences or sequences of similar identity, as well as chromosome interactions which are detectable with a probe that has 70% identity with any sequence / fragment within SEQ ID NO: 1 or with a primer pair that has 70% identity with any sequence / fragment within SEQ ID NO: 51 and 52 . The claims require that these chromosome interactions are “muscular atrophy related,” including diagnostic of muscular atrophy, prognostic of muscular atrophy, or indicative of an individual in need of a therapeutic agent to treat muscular atrophy.
Yet, the disclosure has described a limited number of epigenetic chromosomal interactions that result from two distal regions of a chromosome coming together, which epigenetic chromosomal interactions can be detected using the EpiSwitchTM assay.
With respect to the elected invention, the specification teaches detecting the chromosome interaction on chromosome 2 in which the chromosome regions that come together consist of the sequence of the chromosomal positions 151357305 to 151361853 joining with chromosomal positions 151612320 to 161619007. See, e.g., Example 1 and Table 1a). This chromosome interaction is detected using the ligated nucleic acid probe consisting of SEQ ID NO: 1..
The specification states “The samples were analyzed to identify either an ALS-disease-related diagnostic signature, or the prognostic disease-related signature (at 3 and 6 months). Results of the clinical assessments were compared to the EpiSwitch™ analysis at 0, 3 and 6 months. A cut off of a 0.5-point decline per month of the ALS-FRS-R score was used to cluster the ALS patients into progression-subtypes.”
The specification appears to teach that this “chromosome interaction” detected using the probe of SEQ ID NO: 1 distinguished human subjects having spinal and bulbar muscular atrophy (SBMA) from normal, control human subjects (see Example 1 beginning at para [0229]).
The specification (para [0234] states:
“We have identified top 200 disseminating SBMA-specific CCS, with a False Discovery Rate FDR<0.05. Analysing genetic loci affected by conditional CCS, we performed pathway analysis and demonstrated heavy involvement in SBMA specific profiling of Keratinization (24 genetic loci affected) and Olfactory Transduction (31 genetic loci affected).
The specification (para [0025]) also states:
The invention relates to determining different aspects of muscular atrophy, including in respect to the presence or stage of muscular atrophy. This determining is by typing any of the relevant markers disclosed herein, for example in Table 1, or preferred combinations of markers, or markers in defined specific regions disclosed herein
However, the specification does not teach that the elected probe (or any other particular probe disclosed therein) is correlated with the prognosis of muscular atrophy.
The specification does not disclose in terms of its complete structure or other relevant identifying characteristics a representative number of chromosomal interactions that involve the identified sequences on chromosome 2 which are correlated with an muscular atrophy or which are diagnostic or prognostic of muscular atrophy or whose presence is indicative of an individual who is in need of a therapeutic agent for muscular atrophy.
It is acknowledged that the specification teaches the general methodology for performing assays to detect the ligation of distal chromosomal sequences and for performing the EpiSwitchTM assay. However, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.
Thereby, a showing of how to potentially identify other chromosomal interactions indicative of muscle atrophy, and particularly SBMA, is not sufficient to establish that Applicants were in possession of the invention as broadly claimed.
As noted in Vas-Cath Inc. v. Mahurkar (19 USPQ2d 1111, CAFC 1991), the Federal Circuit concluded that:
"...applicant must also convey, with reasonable clarity to those skilled in art, that applicant, as of filing date sought, was in possession of invention, with invention being, for purposes of "written description" inquiry, whatever is presently claimed."
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision.
With respect to the present invention, there is no record or description which would demonstrate conception of a representative number of additional chromosomal interactions related to or diagnostic or prognostic of muscular atrophy. Therefore, the claims fail to meet the written description requirement because the claims encompass a significantly large genus of chromosomal interactions which are not described in the specification.
Claim Rejections - 35 USC § 102
10. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3-8, 10 and 11 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Akoulitchev et al (WO 2019069067; cited in the IDS of 25 April 2023).
The claims broadly recite a method comprising determining the presence or absence of a muscular atrophy related chromosome interaction “represented by” the elected probe of Table 1 of “Hg38_2_151357305_151361853_151612320_161619007_RF” or the elected probe of SEQ ID NO: 1. As discussed above, it is unclear as to what is encompassed by this language. As broadly recited, the claims encompass methods of detecting the muscular atrophy status of an individual comprising determining the presence or absence of any chromosome interaction involving chromosome 2 sequences using a probe to thereby detect muscular atrophy. The claims encompass methods wherein the muscular atrophy is Amyotrophic Lateral Sclerosis (ALS) since this is a disorder that has the characteristic of muscular atrophy.
Akoulitchev teaches a method for detecting Amyotrophic Lateral Sclerosis (ALS) (i.e., a muscular atrophy status) in an individual comprising determining the presence or absence of a chromosome interaction on chromosome 2 (see, e.g., p. 2, lines 7-24 and Table 1A at p. 40. In particular, Table 1A teaches the following chromosome interaction on chromosome 2:
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In Table 1d at p. 41, Akoulitchev teaches a probe for chromosome 2 that can be used to detect a chromosomal interaction associated with ALS and in Tables 2a and 2b at p. 42, Akoulitchev teaches primers for chromosome 2 that can be used to detect a chromosomal interaction associated with ALS.
Regarding claim 3, Akoulitchev teaches that the method comprises detecting the presence or absence of the chromosome interaction on chromosome 2 in a sample from an individual (e.g., claim 18 therein; and p. 8, lines 4-12).
Regarding claim 4, Akoulitchev teaches that determining the presence or absence of the chromosome interaction comprises (i) in vitro crosslinking of epigenetic chromosomal interactions which are present; (ii) subjecting said cross-linked DNA to cleaving; (iii) ligating said cross-linked cleaved DNA ends to form ligated DNA; and (iv) identifying the presence or absence of said ligated DNA; to thereby determine the presence or absence of the chromosome interaction (e.g., p. 16, lines 3-8).
Regarding claims 5 and 6, these claims further define detecting the ligated DNA but the claims do not require detecting the ligated DNA because the claims encompass the embodiment of claim 3, from which they depend, of only requiring that the chromosome interaction is determined in a sample from an individual. Note, however, that Akoulitchev does teach detecting ligated nucleic acids / DNA using a probe, including a chromosome 2 probe (e.g., p. 13, lines 10-13).
Regarding claim 7, Akoulitchev teaches that the method can be used to diagnose ALS (i.e., a muscular atrophy status; see, e.g., p. 5, lines 25-33).
Regarding claim 8, this claim further defines option (ii) of claim 7 but is not limited to methods that require option (ii). Rather, claim 8 encompasses methods in which, in the method of claim 7, “(iii) the method is carried out to diagnose muscular atrophy.” As discussed above, this limitation is taught by Akoulitchev.
Regarding claim 10, Akoulitchev teaches detecting the presence or absence of one or more chromosome interactions by detecting the ligation product and includes performing quantitative PCR (qPCR) using primers capable of amplifying the ligated product and a probe which binds the ligation site during the PCR reaction, wherein the probe comprises sequence which is complementary to sequence from each of the chromosome regions that have come together in the chromosome interaction (e.g., p. 26, line 15-27).
Regarding claim 11, Akoulitchev teaches that following the identification of the individual as having ALS (a muscular atrophy), the subject is administered a therapeutic agent to treat ALS (i.e., “an anti-muscular atrophy therapeutic agent”; see, e.g., p. 18, line 31 to p. 19, line 2; and p. 26, lines 11-13).
11. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wijesekera et al. (Orphanet journal of Rare Diseases. Biomed Central LTD. 2009. 4(1): p. 1-22; cited in the IDS of 04/25/2023; see p. 2, col. 1) states:
“ALS can be defined as a neurodegenerative disorder characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, brainstem and spinal cord. "Amyotrophy" refers to the atrophy of muscle fibres, which are denervated as their corresponding anterior horn cells degenerate, leading to weakness of affected muscles and visible fasciculations.”
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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