Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of the Claims
Claims 1, 5-6, 9-16 and 18-22 are pending and the subject of this FINAL Office Action.
New Grounds of Rejections - 35 USC § 112- Indefiniteness
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.
Claims 1, 5-6, 9-16 and 18-22 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor the applicant regards as the invention.
Each independent claim, at the point of potential novelty, recites conditions for the pre-selected methylation sites that are confusing. Specifically,
wherein the pre-selected methylation sites are CpG sites selected from genes or regions that show the highest degree of methylation variation during training of the method and have a minimum sequencing coverage of 5x1, wherein genes that have an average methylation level greater than 0.1 or an average methylation level greater than 0.9 are excluded
This condition is self-contradictory, and confusing. First, if all methylation levels greater than 0.1 or 0.9 are excluded, then this excludes, for example, any possible highest degree of methylation variation such as 1.0, 2.0 etc. versus 0. The highest degree of methylation variation is incompatible with the high levels of methylation excluded. Second, it is impossible to determine what 0.1 and 0.9 are measuring because no measure is provided. This seems to be a ratio of some sort (x/y), but neither a denominator nor a numerator is provided. Finally, it is entirely unclear what is excluded because >0.1 includes amounts below 0.9. In other words, the conjunction “or” creates confusion as to the scope of the excluded methylation levels because >0.1 is incompatible with >0.9 as a range. Simply put, is this intended to be a range, or a Markush? If the latter, then Applicants must use proper Markush formatting. See MPEP §§ 2117 & 2173.05(h).
Previous Rejections Maintained
In claims 1 and 10, “significantly similar” is unclear. Specifically, the metes and bounds are unclear. Claim 1 states “wherein if the test methylation profile is significantly similar to one of the one or more predetermined reference methylation profiles, the individual test subject or the individual group of test subjects has a geographical origin similar to the subjects or group of subjects of the one or more predetermined reference methylation profiles.” Claim 10 recites similar language. “Significantly” is not defined in the specification. To this end, it is commonly understood to mean large enough to be noticed or to have an effect. “Similar” means having characteristics in common. The clause therefore reads “the test methylation profile is [large enough to be noticed to have characteristics in common] to one of the one or more predetermined reference methylation profiles.” This is incoherent. It is also a pile of vagueness (large, characteristics, common). It is therefore indefinite.
In claim 5, the “associated with” is unclear because this phrase is inherently vague.
Response to Arguments
The above rejections are maintained because Applicants fail to address the confusion in each issue. The specification does not in fact provide a clear definition of “significantly similar.” When an attempt at a definition of a term uses the term, this is circular. “[S]imilarity observed by statistical means (i.e. by using bioinformatics) and/or also by observation using the eye” completely fails to define with any precision “significantly similar.” Again, what is “significant,” and what is “similar” such that it meets “significantly similar”? The supposed definition proceeds to state that “overlap” of “profiles” is “significant similarity.” Overlap in what way? Quantitative? Qualitative? Both? Mere direction of the data? The fact that one observer “eyes” “good data” that looks “close enough” to other data? What about a second observer? Or third? What is the observers have significant biases (e.g. partial blindness)? Simply put, Applicants’ attempt at a definition only introduces more confusion. Thus, Applicants are very strongly encouraged to amend the claims to recite a specific, concrete measure of “significantly similar,” or delete the phrase.
Applicants completely fail to define “associated,” or address the claim language. Instead they merely state, in circular fashion, “one of ordinary skill in the art would have understood the term [sic] [associated with] to refer to a methylation site whose methylation status is associated with a certain gene being expressed only or predominantly in a certain tissue.” This is not what the claim states. It states “the one or more pre-selected methylation sites in (a) are methylation sites associated with tissue specific gene expression.” Again, no definition of “associated with” is provided. Nor how a methylation site is “associated with” tissue specific gene expression. Is this methylation that merely correlates with any gene? Does the methylation have to be only in a specific tissue? Or does the methylation have to prevent expression of a specific gene in a specific tissue? How close or loose is the “association” between the methylation and the expressed gene? None of this is answered.
Claim Rejection - 35 USC § 112 – Written Description- Maintained
The following is a quotation 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.
Claims 1, 5-6, 9-16 and 18-22 rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain 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, at the time the application was filed, had possession of the full scope of the claimed invention.
The specification fails to demonstrate possession of every methylation profile for every “individual” for every location. “[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.” Noelle v. Lederman, 355 F.3d 1343, 1350 (Fed. Cir. 2004). “Sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010). The Federal Circuit has identified a number of factors to be considered in evaluating the adequacy of disclosures supporting generic claims, including “the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.” Id. at 1351. Here, at best, a single combination is disclosed: certain undisclosed methylation markers are associated with Reilingen Lake, Singlis Lake, Andragnaroa River, and lhosy River in marbled crayfish hepatopancreas or abdominal muscles. No other “individuals,” locations or methylation patterns are disclosed. From this single, very specific example, it is impossible that Applicants possess, for example, the ability to determine the location of a human, or a rat, or a falcon, or a dog, or a worm, or a soybean plant, or a monkey, or a squid, or a sloth.
In fact, even the data in the specification is insufficient for a marbled crayfish location using methylated genes. For example, Table 2 purports to disclose “a core set of 361 variably methylated genes,” any of which can be used to determine the location of a marbled crayfish. However, this is never demonstrated. Instead, all of these methylated sequences (the specification does not disclose to what genes these correspond) where determined merely from crayfish at the same location (Example 2). At best, Example 3 states that Applicants “identified 22 differentially methylated genes (21 overlapping with hepatopancreas) that again allowed a robust separation of the four locations in a principal component analysis,” but never disclose which genes. Example 4 states that “location-specific markers (n=2) were tested with samples from the same two tissues (hepatopancreas and abdominal muscle) and the same four locations (Reilingen, Singlis, Andragnaroa and lhosy), but from new samples, collected one to two years after the first sampling.” However, the data fails to show the ability to determine location of marbled crayfish with any certainty. As shown in Figures 2-3, Example 4 only allows an estimation of location because there is significant overlap of methylated patterns between locations:
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For example, Andragnaroa River and lhosy River data is indistinguishable. Thus, even the data for marbled crayfish does not support the full scope of the locating marbled crayfish in Reilingen Lake, Singlis Lake, Andragnaroa River, and lhosy River.
In sum, the specification fails to demonstrate possession of the claimed invention due to its failure to disclose the ability to locate any organism/individual using any methylated genes.
Response to Arguments
The above rejections are maintained because Applicants still fail to explain how a single methylation combination for a single species demonstrates possession of an assay for determining geographic origin using any methylation profile for any invertebrate, fish or bird. Although Applicants argue that Examples 5 and 6 also disclose methylation profiles in chickens and coho salmon, yet neither example provides the methylation sites, which are critical to determining if Applicants possessed the claimed assay. This a serious deficiency for a claim that encompasses the claimed assay applied to any and all methylation sites. Further, no locations are provided for these examples. Applicants have completely failed to disclose any actual methylation profiles to demonstrate that they possess their claimed assay. At best, Applicants have used conventional, known assays to determine a methylation profile for crayfish in specific locations, yet, just like for chickens and coho salmon, critically fail to disclose what is that methylation profile and how it is different from the prior art. Thus, Applicants have fallen far short of their duty to disclose their invention 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.” Simply put, a skilled artisan could not determine whether the claimed assay actually distinguishes geographical origins of organisms because no methylation profiles are provided to verify. The claimed assay appears to be a wish or a plan without this critical data.
Note on Prior Art
Metzger et al, The DNA Methylation Landscape of Stickleback Reveals Patterns of Sex Chromosome Evolution and Effects of Environmental Salinity, Genome Biol Evol. 2018 Mar 1;10(3):775-785. doi: 10.1093/gbe/evy034.
As explained in the Non-Final, Metzger teaches a method of distinguishing locations using methylation profiles in fish. One location has a salinity “parameter” different from the other. A skilled artisan would understand that any “parameter” could affect methylation, meaning this cannot be the basis of allowability. In other words, Metzger in fact teaches that a methylation profile from one salinity location can be different from another salinity location, allowing one to distinguish the location of a fish based on the methylation profile. This requires one to determine a methylation profile of each location. This profile is used to determine a samples’ origin or location. It is simply untrue that Metzger, as read by a skilled artisan, does not teach using a “predetermined reference methylation profile” to identify geographic origins or asses environmental parameters. Applicants have misconstrued Metzger because they insist on the exact same language as their claims. However, a skilled artisan, with basic biological training and common sense would immediately see in Metzger the claimed assay.
Furthermore, Metzger teaches to develop location-based methylation profiles using bisulfite sequencing, just like here. In fact, Metzger uses high-coverage analysis just like here (pg. 777, citing Ziller et al). Metzger would also have used, based on simple common sense of a skilled artisan, the highest methylation variability in order to most clearly distinguish sites/locations.
The only issue that the Examiner cannot resolve due to Applicants’ confusing claims is the methylation degree required, as explained in the indefiniteness rejection above.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681
1 To the extent high coverage is intended, this is not new, and is not the basis for any allowable subject matter. See e.g. Ziller et al, Coverage recommendations for methylation analysis by whole genome bisulfite sequencing, Nat Methods. 2014 Nov 2;12(3):230–232. doi: 10.1038/nmeth.3152.
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