DETAILED ACTION
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 .
Applicant’s election without traverse of Group I, SEQ ID NO: 59, 5’-tRFs, and breast cancer in the reply filed on 6/22/2026 is acknowledged.
Claims 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected subject (a non-elected invention or non-elected species), there being no allowable generic or linking claim.
Claims 2 and 9 have been examined to the extent that the claims read on 5’-tRFs. The additionally recited fragment types have been withdrawn from consideration as being directed to a non-elected species. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claims 5 and 21 have been examined to the extent that the claims read on the elected sequence (SEQ ID NO: 59). The additionally recited sequences have been withdrawn from consideration as being directed to a non-elected species. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4-9, 11-15 and 20-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite a correlation between tRNAHisGTG fragments and a diagnosis of a disease or condition. For example the claims recite a correlation between SEQ ID NO: 59 and risk of a disease or condition that is breast cancer. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
Claim 20 additionally recites the correlation between relative abundance of tRNA fragment and the “cell’s tissue of origin.” This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. The claims are drawn to a method of “identifying” a subject in need of therapeutic intervention to treat a disease or condition, disease recurrence or disease progression (clm 1). The broadest reasonable interpretation of the “identifying” is that it may be accomplished by a mental processes. For example, one may “identify” the subject in need of therapeutic intervention by thinking about the tRNAHisGTG signature.
Additionally the claims recite a step of “characterizing” the tRNAHisGTG and their relative abundance in the sample to identify a signature (clms 1 and 20). Neither the specification nor the claims set forth a limiting definition for “characterizing” and the claims do not set forth how this step is accomplished. The claims do not clearly require performing any “wet” laboratory steps to make the characterization. The broadest reasonable interpretation of “characterizing” is that it encompasses abstract data analysis, that is a mental process abstract idea.
Additionally the claims recite wherein when the signature is indicative of a diagnosis of the disease, condition, disease recurrence or disease progression, a treatment is recommended (clm 1). The broadest reasonable interpretation of “recommending” a treatment is thinking about what treatment a subject should take. Thinking is an abstract mental process.
The claims are drawn to a method of “diagnosing, identifying or monitoring” a disease or condition in a subject in need thereof (clm 14). The broadest reasonable interpretation of the “diagnosing, identifying or monitoring” is that it may be accomplished by a mental processes. For example, one may “diagnose, identify or monitor” a disease/condition by thinking about the presence/absence of a tRNAHisGTG.
The claims recite a step of “analyzing levels of the tRNAHisGTG fragment present in the cell; wherein a differential in the measured tRNAHisGTG fragment levels compared to a reference is indicative of a diagnosis or identification of breast cancer in the subject. The broadest reasonable interpretation of this step is that it may be accomplished by a mental processes. It is noted that several court cases have found steps of “comparing” to be abstract.
The claims are drawn to a method of “identifying” a cell's tissue of origin to treat and/or prevent a disease or condition, disease recurrence, or disease progression in a subject in need thereof (clm 20). The broadest reasonable interpretation of the “identifying” is that it may be accomplished by a mental processes. For example, one may “identify” the cells tissue of origin by thinking about the cells tRNAHisGTG signature.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
It is noted that the steps of “characterizing” (to the extent that it encompasses non-abstract steps) in claims 1 and 20 and “hybridizing” in claim 14 are not considered to integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
Further it is noted that claims 14 and 20 recite a step of “providing” a treatment regimen to the subject. The treating step is not particular, and is instead merely instructions to apply the judicial exception in a generic way. Thus, the treatment step does not integrate the mental analysis steps into a practical application.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims recite a step of “characterizing” at least one tRNAHisGTG fragment and its relative abundance (see clms 1 and 20) and a step of “hybridizing” a tRNAHisGTG fragment to a panel of oligos engineered to detect the tRNAHisGTG fragment (clm 14). These steps do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art to the judicial exceptions.
The step of “characterizing” tRNAHisGTG fragment is recited at a high level of generality. This step merely instructs a scientist to use any method known in the art to characterize the tRNAHisGTG fragment. The hybridizing step does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes these steps from well understood, routine, and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally the teachings in the specification demonstrate the well understood, routine, conventional nature of the additional elements because it teaches that the additional elements are well known or commercially available. For example the specification teaches the following:
[0129]The tRNA fragments may be isolated by a method known in the art or selected from the group consisting of size selection, sequencing, amplification. The tRNA fragments may be quantified by a method known in the art or selected from dumbbell-PCR, FIREPLEX.RTM., miR-ID.RTM., or related.
[0137] The practice of the present invention employs, unless otherwise indicated conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are well within the purview of the skilled artisan. Such techniques are explained fully in the literature, such as, "Molecular Cloning: A Laboratory Manual," fourth edition (Sambrook, 2012); "Oligonucleotide Synthesis" (Gait, 1984); "Culture of Animal Cells" (Freshney, 2010); "Methods in Enzymology" "Handbook of Experimental Immunology" (Weir, 1997); "Gene Transfer Vectors for Mammalian Cells" (Miller and Calos, 1987); "Short Protocols in Molecular Biology" (Ausubel, 2002); "Polymerase Chain Reaction: Principles, Applications and Troubleshooting", (Babar, 2011); "Current Protocols in Immunology" (Coligan, 2002). These techniques are applicable to the production of the polynucleotides and polypeptides of the invention, and, as such, may be considered in making and practicing the invention. Particularly useful techniques for particular embodiments will be discussed in the sections that follow.
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available. For example see the prior art rejections set forth below.
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(b)
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 1-2, 4-9, 11-15 and 20-22 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.
Regarding Claims 1-2, 4-9, 11-13 and 22 it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method of identifying a subject in need to therapeutic intervention to treat a disease or condition, disease recurrence, or disease progression, yet the method only requires characterizing the tRNAHisGTG fragment and its relative abundance in the sample to identify a signature. Thus it is not clear if applicant intends to cover only a method of characterizing the tRNAHisGTG fragment and its relative abundance in the sample to identify a signature OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims. It is noted that the claims further recite “wherein when the signature is indicative of a diagnosis of the disease, condition, disease recurrence or disease progression, a treatment of the subject is recommended”. However Applicants are reminded that claim scope is not limited by claim language (such as “wherein” clauses) that suggests or makes optional but does not require steps to be performed.
Claim 6 is indefinite because it is unclear how, when characterizing the abundance of a fragment, the skilled practitioner is to ascertain that a particular modification occurred “post transcription” such that the fragment is post-transcriptionally modified. For example the specification teaches that tRFs with a uracil at the -1 position could either be the result of posttranscriptional enzymatic action or the result of cleavage of the precursor of tRNA (p. 29 of WO 2017/136760). It is unclear what further action is required to practice the invention relative to the independent claim.
Claim 7 recites that the “tRNAHisGTG fragment interacts with Argonaute” but it is unclear when this interaction is meant to occur. That is, it is unclear if the fragment must be interacting with Ago in the sample cells, or if this is referring to a theoretical interaction or the possibility of interaction. Furthermore, it is unclear if the claim is intended to require that the interaction be measured or detected, or how a skilled practitioner characterizing a fragment relative abundance would know that the fragment interacts with Ago.
Claim 9 is indefinite when it recites “wherein the relative abundance is high in a hormone dependent cancer” because it is not clear how this clause is meant to limit the claim which does not previously mention any cancer, and which does not integrate this “wherein” clause with any action or activity in the claim. The clause is unconnected to the rest of the claim.
Regarding claims 14-15 it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method of diagnosing, identifying, or monitoring a disease or condition in a subject in need thereof, yet the method only requires hybridizing a tRNAHisGTG fragment obtained from a cell obtained from the subject to a panel of oligonucleotides engineered to detect the tRNAHisGTG; analyzing levels of the tRNAHisGTG fragment present in the cell; and providing a treatment regimen to the subject dependent on the differential in the measured tRNAHisGTG fragment levels to the reference. Thus it is not clear if applicant intends to cover only a method of hybridizing a tRNAHisGTG fragment obtained from a cell obtained from the subject to a panel of oligonucleotides engineered to detect the tRNAHisGTG; analyzing levels of the tRNAHisGTG fragment present in the cell; and providing a treatment regimen to the subject dependent on the differential in the measured tRNAHisGTG fragment levels to the reference OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims. It is noted that the claims further recite “wherein a differential in the measured tRNAHisGTG fragment levels compared to a reference is indicative of a diagnosis or identification of breast cancer in the subject”. However Applicants are reminded that claim scope is not limited by claim language (such as “wherein” clauses) that suggests or makes optional but does not require steps to be performed.
Claim 15 is rejected over the recitation of the phrase “wherein the disease or condition is a cancer selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, prostate cancer, liver cancer and eye cancer”. This recitation is confusing because claim 15 depends from claim 14 which states that the cancer is breast cancer. Therefore it’s unclear how claim 15 further limits the method of claim 14. Clarification is required.
Regarding Claims 20-21 it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method of identifying a cell's tissue of origin to treat and/or prevent a disease or condition, disease recurrence, or disease progression, yet the method only requires characterizing the tRNAHisGTG fragment and its relative abundance in the sample to identify a signature; and providing a treatment regimen to the subject. Thus it is not clear if applicant intends to cover only a method of characterizing the tRNAHisGTG fragment and its relative abundance in the sample to identify a signature; and providing a treatment regimen to the subject OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims. It is noted that the claims further recite “wherein the signature is indicative of the cell's tissue of origin”. However Applicants are reminded that claim scope is not limited by claim language (such as “wherein” clauses) that suggests or makes optional but does not require steps to be performed. Claim 20 is further problematic because it recites providing a treatment regimen to the subject dependent on the cell’s tissue of origin, yet there is no active process step of determining the cells tissue of origin.
Claim Rejections - 35 USC § 112(a)
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 1-2, 4-9, 11-15 and 20-22 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
In analyzing the claims for compliance with the written description requirements of 35 U.S.C. 112, first paragraph, a determination is made as to whether the specification contains a written description sufficient to show they had possession of the full scope of their claimed invention at the time the application was filed.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
In the present situation, the claims are drawn to methods of (i) identifying a subject in need of therapeutic intervention to treat a disease or condition, disease recurrence, or disease progression (clm 1); diagnosing, identifying or monitoring a disease or condition in a subject (clm 14); and identifying a cells tissue of origin (clm 20) based on the characterization and analysis of at least one tRNAHisGTG fragment. The claims recite a correlation between the at least one tRNAHisGTG fragment and the disease/condition or the cells tissue of origin. The claims do not describe the tRNAHisGTG fragments that are correlated with a disease/condition or the cells tissue of origin in terms of any relevant identifying characteristics. The size of the genus is vast given the number of possible tRNAHisGTG fragments that are present in the human transcriptome and genome.
The size of the genus is further expanded by the fact that the claims encompass detecting tRNAHisGTG fragments in human subjects and non-human subjects. The specification (para 0005) teaches that the composition and abundance of tRF’s depend on a person’s gender, population, and race. It follows that the identity of tRNAHisGTG fragments useful in the claimed methods would be expected to be variable between species.
Additionally, the size of the claimed genus of tRNAHisGTG fragments is further increased by the fact that the claims encompass tRNAHisGTG fragments that are diagnostic of ANY disease or condition, including such diverse diseases as Alzheimer’s disease, glaucoma, breast cancer, lupus, asthma, eczema, rheumatoid arthritis etc. The specification (para 0005) teaches that the composition and abundance of tRF’s depends on disease and disease subtype. Accordingly, the identity of diagnostic rRNA fragments would be expected to be variable between different diseases or conditions.
Additionally, the size of the claimed genus of tRNAHisGTG fragments is further increased by the fact that the claims encompass tRNAHisGTG fragments that indicative of the origin of ANY cell type. The specification (para 0005) teaches that the composition and abundance of tRF’s depend on tissue type and tissue state.
Additionally, the size of the claimed genus of tRNAHisGTG fragments is further increased by the fact that the disclosure is very broad in defining tRNAHisGTG fragments, stating that the term “tRNAHisGTG” is “functional short non-coding RNAs generated from a tRNA locus.” The definition is sufficiently broad to encompass any functional, short non-coding RNA generated from a tRNA, no matter the locus. This definition is broader than the plan language of the claim which suggests fragments from the HisGTG locus, but the specification must inform the broadest reasonable interpretation of the claims. See specification p. 18, line 5 and following.
Further, the claims include isolating tRNAHisGTG fragments from any type of sample type (i.e., amniotic fluid, bile, blood, breast milk, lymph, smegma, vomit etc.) The specification (para 0005) teaches that the composition and abundance of tRF’s depend on tissue type and tissue state. Thus the presence and levels of particular rRNA vary significantly between different sample types.
The specification (para 0143) teaches that the inventors performed an analysis of 10,274 normal and disease samples of the Cancer Genome Atlas Repository.
The specification (para 0146) teaches that the analysis of the 10,274 datasets mentioned above herein generated 20,722 distinct tRFs above threshold. Of interest are those fragments that overlap the mature tRNA of HisGTG. Specifically, the 66 tRFs that begin at position -1 of isodecoders of tRNAHisGTG (FIG. 12, SEQ ID NOs: 1-66), 21 tRFs that begin at position +1 of isodecoders of tRNAHisGTG (FIG. 13, SEQ ID NOs: 67-87), and the 771 tRFs that begin at positions other than -1 or +1 (FIGS. 14A-14K, SEQ ID NOs: 88-858).
While the specification discloses tRNAHisGTG fragments that are differentially expressed in normal and various types of cancer, this is not equivalent to disclosing a representative number of species of the claimed genus of rRNA fragments diagnostic of ANY type of disease/condition in any human or non-human subject.
Accordingly, the specification has not described by its complete structure or any other relevant identifying characteristics a representative number of tRNAHisGTG fragments of a representative number of different diseases/conditions.
It is noted that the specification also teaches the general methodology for comparing tRNAHisGTG fragment abundance in terms of reads per million (RPM) expression in normal samples and cancer samples. 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. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
This finding is also emphasized in Ex Parte Kubin (No. 2007-0819, Bd. Pat. App. & Int. May 31, 2007), wherein it is stated that:
“Although there is often significant overlap” between the enablement and written description requirements, “they are nonetheless independent of each other.” University of Rochester, 358 F.3d at 921, 69 USPQ2d at 1891. An “invention may be enabled even though it has not been described.” Id. Such is the situation here. While we conclude that one skilled in the art would have been able to make and use the full scope of claim 73 through routine experimentation, we find Appellants did not describe the invention of claim 73 sufficiently to show they had possession of the claimed genus of nucleic acids. See, e.g., Noelle v. Lederman, 355 F.3d 1343, 1348, 69 USPQ2d 1508, 1513 (Fed. Cir. 2004) (“invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed”).
Thereby, a showing of how to potentially identify other tRNAHisGTG fragments associated with ANY disease/condition is not sufficient to establish that Applicants were in possession of the invention as broadly claimed.
Moreover, the naming of an tRNAHisGTG fragment terms of its functional attributes is not sufficient to describe that tRNAHisGTG fragment. More than a statement of biological function is required to satisfy the 35 USC 112 first paragraph, written description requirement for a genus of DNA molecules. See e.g. Amgen Inc. v. Chuzai Pharmaceutical Co. Ltd., 18 U.S.P.Q.2d 1016, 1027 (CAFC 1991); and Fiers v. Revel, 25 U.S.P.Q.2d 1601, 1604-05 (CAFC 1993). In Amgen v. Chuzai, the Court of Appeals for the Federal Circuit stated that "it is not sufficient to define (a DNA) solely by its principal biological property, e.g. encoding of human erythropoietin." Id. at 1021. Rather, what is necessary is that (the applicant) provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims." Id. at 1027. In these statements, the court has expressly stated that a DNA molecule must be described by means of description other than by naming the encoded protein to satisfy the 35 USC 112 first paragraph written description requirement.
As the District Court in University of Rochester v. G.D. Searle & Co., Inc. (2003 WL 759719 W.D.N.Y.) noted “In effect, then, the '850 patent claims a method that cannot be practiced until one discovers a compound that was not in the possession of, or known to, the inventors themselves. Putting the claimed method into practice awaited someone actually discovering a necessary component of the invention.” This is similar to the current situation since the breadth of the current claims comprises any tRNAHisGTG fragment diagnostic of ANY disease/condition from any organism which the present inventors were not in the possession of, or which were not known to the inventors.
Additionally, Cf. University of Rochester v G.D. Searle & Co., Inc., Monsanto Company, Pharmacia Corporation, and Pfizer Inc., No. 03-1304, 2004 WL 260813 (Fed. Cir., Feb. 13, 2004) held that:
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.
Also 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 tRNAHisGTG fragments within the broadly claimed genus of tRNAHisGTG fragments diagnostic of ANY disease/condition. Therefore, the claims fail to meet the written description requirement because the claims encompass a significantly large genus of tRNAHisGTG fragments which are not described in the specification.
Claims 1-2, 4-9, 11-15 and 20-22 are rejected under 35 U.S.C. 112, 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.
Breadth of the Claims:
In the present situation, the claims are drawn to methods of (i) identifying a subject in need of therapeutic intervention to treat a disease or condition, disease recurrence, or disease progression (clm 1); diagnosing, identifying or monitoring a disease or condition in a subject (clm 14); and identifying a cells tissue of origin (clm 20).
The methods require characterizing at least one tRNAHisGTG fragment and its relative abundance in a sample to identify a signature.
The claims state that (i) when the signature is indicative of a diagnosis of the disease, condition, disease recurrence or disease progression, treatment is recommended (clm 1), (ii) wherein a differential in the measured tRNAHisGTG fragment levels compared to a reference is indicative of a diagnosis or identification of breast cancer (clm 14); and (iii) wherein the signature is indicative of the cells tissue of origin (clm 20).
The claims do not describe the tRNAHisGTG fragments that are correlated with a disease/condition or the cells tissue of origin in terms of any relevant identifying characteristics. The size of the genus is vast given the number of possible tRNAHisGTG fragments that are present in the human transcriptome and genome.
The claims do not specify a particular disease or condition. Rather, the claims encompass ANY disease/condition, including such diverse diseases as Alzheimer’s disease, glaucoma, breast cancer, lupus, asthma, eczema, rheumatoid arthritis etc. These diseases differ with respect to their symptoms, etiologies, and outcomes.
The claims encompass methods wherein the tRNAHisGTG fragment are obtained from a sample from a subject. In view of the recitation of “subject” the claims encompass both human and non-human subjects (i.e., dogs, cats, horses, monkeys, rats, pigs rabbits etc.). Only claim 22 is limited to humans.
The claims also encompass methods wherein the tRNAHisGTG fragment are isolated from ANY sample type. Claim 11 states that the sample type can be amniotic fluid, aqueous humor and vitreous humor bile, blood serum, breast milk, cerebrospinal fluid, cerumen, chyle, chyme, endolymph and perilymph, exudates, feces, female ejaculate, gastric acid, gastric juice, lymph, mucus, pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, sebum, serous fluid, semen, smegma, sputum, synovial fluid, sweat, tears, urine, vaginal secretion, and vomit.
Additionally, the claims also encompass methods whrein the tRNAHisGTG fragments is from any locus. The disclosure is very broad in defining tRNAHisGTG fragments, stating that the term “tRNAHisGTG” is “functional short non-coding RNAs generated from a tRNA locus.” The definition is sufficiently broad to encompass any functional, short non-coding RNA generated from a tRNA, no matter the locus. This definition is broader than the plan language of the claim which suggests fragments from the HisGTG locus, but the specification must inform the broadest reasonable interpretation of the claims. See specification p. 18, line 5 and following.
Nature of the Invention
Thus the nature of the invention requires a reliable correlation between tRNAHisGTG fragments and a disease/condition. The invention is in a class of inventions which the CAFC has characterized as 'the unpredictable arts such as chemistry and biology" (Mycolgen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Federal Circuit 2001)).
Teachings in the Specification and Examples:
The specification (para 0143) teaches that the inventors performed an analysis of 10,274 normal and disease samples of the Cancer Genome Atlas Repository.
The specification (para 0146) teaches that the analysis of the 10,274 datasets mentioned above herein generated 20,722 distinct tRFs above threshold. Of interest are those fragments that overlap the mature tRNA of HisGTG. Specifically, the 66 tRFs that begin at position -1 of isodecoders of tRNAHisGTG (FIG. 12, SEQ ID NOs: 1-66), 21 tRFs that begin at position +1 of isodecoders of tRNAHisGTG (FIG. 13, SEQ ID NOs: 67-87), and the 771 tRFs that begin at positions other than -1 or +1 (FIGS. 14A-14K, SEQ ID NOs: 88-858).
The Predictability or Unpredictability of the Art:
The art of determining an association between tRNAHisGTG fragments and the occurrence of a phenotype, such as a disease/condition, is highly unpredictable. It is highly unpredictable as to which of the vast number of possible tRNAHisGTG fragments are specifically diagnostic of any particular disease/condition.
In the present situation, the specification does not exemplify any methods wherein one or more tRNAHisGTG fragments diagnostic of a disease/condition are detected in a sample obtained from a subject and this information is used to effectively diagnose the disease/condition. All examples provided in the specification are prophetic.
While the specification discloses tRNAHisGTG fragments that are differentially expressed in normal samples and cancer samples, this is not equivalent to disclosing a representative number of species of the claimed genus of tRNAHisGTG fragments diagnostic of ANY type of disease/condition in any human or non-human subject.
In the instant case it is highly unpredictable if the tRNAHisGTG fragments disclosed in cancer cells of human patients with cancer will be more abundant in other types of samples (non-cancerous cells) obtained from these human patients. The specification (para 0005) teaches that the levels and compositions of tRNAHisGTG depends on the tissue and the tissue state. Accordingly, the presence or abundance of tRNAHisGTG fragments in other sample types is not predictable based on the teachings in the specification.
There is also a high level of unpredictability in the art of extrapolating the findings concerning changes in the abundance of tRNAHisGTG fragments associated with one specific disease/condition to other diseases/conditions. The claims encompass tRNAHisGTG fragments that are diagnostic of ANY disease or condition, including such diverse diseases as Alzheimer’s disease, glaucoma, breast cancer, lupus, asthma, eczema, rheumatoid arthritis etc. The specification (para 0005) teaches that the levels and composition of tRNAHisGTG fragments depends on disease and disease subtype. Accordingly, the identity of additional diagnostic tRNAHisGTG fragments for other diseases is not predictable based on the teachings in the specification.
Additionally, the claims encompass the diagnosis of both human and non-human subjects. The art of extrapolating tRNAHisGTG fragment abundance is highly unpredictable. The specification (para 0005) teaches that the levels and composition of tRNAHisGTG fragments depend on a person’s sex, a person’s population origin, and a person’s race. It follows that the identity of diagnostic tRNAHisGTG fragments would be expected to be variable between species. In other words it is highly unpredictable if tRNAHisGTG fragments that are diagnostic of a particular disease in humans would also be diagnostic of that same disease in birds, dogs, horses, etc.
Further it is relevant to note the post filing date art of Sun (Cancer Letters 414 (2018) pages 16-25). Sun teaches that the aberrant expression of tRNA-derived fragments in cancer may act as a potential diagnostic biomarker or therapeutic target (page 1, col 2). Sun teaches that since development of genome sequencing technology, tRNA-derived fragments have been observed in a number of human diseases including cancer, infection, neurodegeneration and other pathological conditions. Sun teaches that in different types of cancer, the expression of tRNA-derived fragments is different. More recently, Carlo M. Croce et al. designed a microarray chip to examine the expression of tRF-1 series (tsRNAs) in different tumor samples including chronic lymphocytic leukemia (CLL), lung cancer, colorectal cancer, breast cancer and ovarian cancer. Through these analyses, they identified signatures of tsRNAs in each of these cancers. They also identified a signature of 31 tsRNAs can discriminate among different cancers and tissue types (page 20, col 1). Sun teaches that the expression and biological functions of tRNA-derived fragments are strikingly different in different type of cancers. The factors that influence the expression of tRNA-derived fragments in different cancers are quite unclear. As the expression abundance of tRNA-derived fragments differs greatly in different cell types and cancer tissues, it is unknown how their expression correlates with cell and tissue specificity, and whether tRNA modifications affect the production of tRNA-derived fragments. These topics still require further in-depth investigation. Currently, the mechanism of how tRNA-derived fragments regulate cancer progression is limited and still in the initial phase. Sun teaches that some of the newly identified tRNA-derived fragments could represent a new diagnostic tool in cancer management. However, these tRNA-derived fragments have not been applied in clinical practice. Thus, an additional challenge for cancer biologists in the years ahead will be the identification of tRNA-derived fragments as novel biomarkers and targeted therapies in cancer (page 23 col 1-2). Based on the teachings of Sun it appears that even after the filing date of the present application, scientists are just beginning to investigate and consider the relevance of tRNA fragments.
Quantity of Experimentation and Amount of Direction or Guidance Provided by the Specification:
The specification does not provide any specific guidance as to how to predictably identify particular tRNAHisGTG fragments that are diagnostic of particular disease or condition. There is no common structure for the tRNAHisGTG fragments which would guide the artisan as to how to predictably identify tRNAHisGTG for a particular disease or condition.
The specification does not provide sufficient guidance as to how to predictably extrapolate any findings from human subjects to a representative number of non-human subjects, how to predictably extrapolate the findings obtained for a particular disease/condition to other diseases/conditions, or how to predictably extrapolate the findings obtained in particular sample types to other sample types.
Extensive experimentation would be required to practice the claimed invention. Such research would require, for example, identifying tRNAHisGTG fragments that are differentially expressed in subjects that have one type disease as compared to normal, healthy control subjects and then performing experiments in large populations in order to establish that the differences in the tRNAHisGTG expression levels are the same in the larger population and are statistically significant. The experimentation would further require practicing the above method in a representative number of different organisms, and in subjects having a representative number of different diseases/conditions, as well as in a representative number of different samples. The results of such experimentation are highly unpredictable and the experimentation is extremely extensive.
Applicants attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Herein, there is an extensive and excessive amount of experimentation that would be required to practice the broadly claimed invention.
Conclusions:
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."
Moreover, 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".
In the present situation, Applicants have not established that tRNAHisGTG fragments are diagnostic of any disease/condition and are present at different levels in samples obtained from a subject such that they can be used to diagnose any disease/condition. Further, there is insufficient disclosure regarding the identity of a representative number of tRNAHisGTG fragments that are associated with a representative number of diseases/conditions. In view of the unpredictability in the art, and the lack of disclosure and guidance provided in the specification and in the prior art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
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 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.
It is noted that claims rejected in this portion of the Office Action under 35 USC 102 and 103 as anticipated by, or obvious in view of, the prior art have been previously rejected in this Office Action under 35 USC 112 1st paragraph as not fully described or enabled by the specification as originally filed. In the instant case, where the prior art does anticipate and render obvious particular embodiments of the broadly claimed methods, the prior art is not sufficient to provide an adequate written description of the breadth of the claims, nor is the prior art sufficient to enable the skilled artisan to practice the claimed method in the full scope of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 4, 11, 12, 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li (Molecular and Cellular Biology AACR 104th Annual Meeting 2013; Apr 6-10, 2013).
Regarding Claim 1 it is noted that MPEP 2111.02 states, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” In the present situation, the process steps are able to stand alone and the preamble limitation is not accorded patentable weight. Accordingly, the claim language of “A method of identifying a subject in need of therapeutic intervention to treat a disease, condition, disease recurrence, or disease progression” merely sets forth the purpose of the process, but does not limit the scope of the claims.
Regarding Claim 1 Li teaches that they characterized 5′-tRFHis-GTG, a novel tRNA-derived novel miRNA-like smRNA, in renal cell carcinoma (RCC) metastasis. Li teaches that they examined 5′-tRFHis-GTG expression profiles in benign kidney tissue, localized and metastatic RCCs in a frozen tissue cohort (n=24) by smRNA-seq. Li teaches validation of the differential expression of 5′-tRFHis-GTG in a 237-specimen FFPE tissue cohort of localized and metastatic RCCs by RT-PCR. Li teaches that 5′-tRFHis-GTG has been found to be up-regulated in metastatic RCCs, comparing to the localized tumors in the 24-sample frozen tissue cohort. Validation test using a separate FFPE tissue cohort of 237 clinical specimens confirmed the upregulated 5′-tRFHis-GTG expression in metastatic RCC tissues. Li teaches that 5′-tRFHis-GTG, a novel tRNA-derived miRNA-like smRNA that is probably induced by oxidative stress, is upregulated in metastatic RCCs and involved in metastatic tumor cell proliferation and migration (abstract). Thus Li teaches a method comprising characterizing a tRNAHisGTG fragment and its relative abundance isolated from a sample obtained from the subject to identify a signature. It is noted that Li teaches all of the claimed active process steps. Li does not teach “wherein when the signature is indicative of a diagnosis of the disease, condition, disease recurrence, or disease progression, treatment of the subject is recommended”. However this art rejection is set forth because it teaches a broad interpretation of the claims which does not require recommending treatment. Applicants are reminded that claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed.
Regarding Claim 2 Li teaches a method wherein the tRNAHisGTG is a 5’-tRNA fragment (5’-tRF) (abstract).
Regarding Claim 4 Li teaches that the 5′-tRFHis-GTG is a 24 mer RNA fragment derived from the mature form of tRNA-HIS(GTG) (abstract).
Regarding Claims 11 and 12 Li teaches a method wherein sample is isolated from tissue obtained from the subject (abstract). Note that while claim 12 further defines the body fluid the claim, considered in its entirety, does not require that the sample is isolated from a body fluid.
Regarding Claim 13 Li teaches a method wherein the sample is a tumor cell since tumor tissues are comprised of tumor cells (abstract).
Claims 1-2, 4, 5, 9, 11, 12, 13 and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Honda et al. (PNAS 2015 E3816-3825).
Regarding Claim 1 it is noted that MPEP 2111.02 states, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” In the present situation, the process steps are able to stand alone and the preamble limitation is not accorded patentable weight. Accordingly, the claim language of “A method of identifying a subject in need of therapeutic intervention to treat a disease, condition, disease recurrence, or disease progression” merely sets forth the purpose of the process, but does not limit the scope of the claims.
Regarding Claim 1 Honda teaches that they characterized 5′-tRFHis-GTGin actual breast cancer patient tissues by TaqMan qRT-PCR. See p. E3821-22. Thus Honda teaches a method comprising characterizing a tRNAHisGTG fragment and its relative abundance isolated from a sample obtained from the subject to identify a signature. It is noted that Honda teaches all of the claimed active process steps. Honda reports detecting the fragment in ER+ BC but not TNBC or normal tissue , see Figure 7A. Honda does not teach “wherein when the signature is indicative of a diagnosis of the disease, condition, disease recurrence, or disease progression, treatment of the subject is recommended”. However this art rejection is set forth because it teaches a broad interpretation of the claims which does not require recommending treatment. Applicants are reminded that claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed.
Regarding Claim 2 Honda teaches a method wherein the tRNAHisGTG is a 5’-tRNA fragment (5’-tRF) (p. 3822).
Regarding, Claim 4 the tRNA-HIS(GTG) is between 15 and 80 nucleotides, see Figure 2E (abstract).
Regarding claim 5, the supplemental data teaches that the probe for the human 5’tRNAhisgug half comprises the complement of instant SEQ ID NO: 59, thus evidencing that the tRNA fragment detected comprises SEQ ID NO: 59. See Table S2.
Regarding claim 9, the 5’tRNA is high in ER+ cancer.
Regarding Claims 11 and 12 Honda teaches a method wherein sample is isolated from tissue obtained from the subject (p. 3821). Note that while claim 12 further defines the body fluid the claim, considered in its entirety, does not require that the sample is isolated from a body fluid.
Regarding Claim 13 Honda teaches a method wherein the sample is a tumor cell since tumor tissues are comprised of tumor cells (p. 3821).
Regarding claim 22, the real breast cancer patients were humans.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Li (Molecular and Cellular Biology AACR 104th Annual Meeting 2013; Apr 6-10, 2013) in view of Katibah (PNAS Aug 19, 2014 Vol 111 No 33 pages 12025-12030).
The teachings of Li are presented above.
Li does not teach a method wherein the tRNA-HIS(GTG) fragment is post-transcriptionally modified with at least one selected from the group consisting of guanylation, uridylation, adenylation, P, cP, OH, and aa (clm 6). Regarding claim 7, Li teaches that the tRNA was isolated following precipitation with Ago2.
However Katibah teaches that HisGTG is post transcriptionally modified with a 5’ guanosine addition (page 12029, col 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Li by detecting HisGTG is post transcriptionally modified with a 5’ guanosine addition as suggested by Katibah. In particular Katibah teaches that this particular modification is expected. Thus it would have been obvious to include detecting tRNA-HIS(GTG) fragment that have been modified with guanylation since this appears to be an expected post transcriptional modification.
Claims 22 is rejected under 35 U.S.C. 103 as being unpatentable over Li (Molecular and Cellular Biology AACR 104th Annual Meeting 2013; Apr 6-10, 2013) in view of Katibah (PNAS Aug 19, 2014 Vol 111 No 33 pages 12025-12030) as applied to claim 6 above and in further view of Anderson (FEBS Letters 588 (2014) 4297-4304).
The teachings of Li and Katibah are presented above.
The combined references do not teach a method wherein the subject is a human (clm 22).
However Anderson teaches that the levels of tRNAs vary widely among normal (non-diseased) human tissues (the level of variation is as much as tenfold) (page 4300, col 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Li and Katibah by detecting tRFHisGTG fragments samples obtained from humans as suggested by Anderson. In particular Anderson teaches that the levels of tRNAs vary widely among normal (non-diseased) human tissues (the level of variation is as much as tenfold) (page 4300, col 2). One of skill in the art would have been motivated to detect tRNA fragments samples of human subjects to further study if they can be used as biomarkers for detecting human diseases.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Li (Molecular and Cellular Biology AACR 104th Annual Meeting 2013; Apr 6-10, 2013) in view of Thompson (RNA 2008 14:2095-2103) and Hutson (The Oncologist 2011; 16(suppl 2):14-22.
Regarding Claim 14 it is noted that MPEP 2111.02 states, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” In the present situation, the process steps are able to stand alone and the preamble limitation is not accorded patentable weight. Accordingly, the claim language of “A method of diagnosing, identifying, or monitoring a disease or condition” merely sets forth the purpose of the process, but does not limit the scope of the claims.
Regarding Claim 14 Li teaches that they characterized 5′-tRFHis-GTG, a novel tRNA-derived novel miRNA-like smRNA, in renal cell carcinoma (RCC) metastasis. Li teaches that they examined 5′-tRFHis-GTG expression profiles in benign kidney tissue, localized and metastatic RCCs in a frozen tissue cohort (n=24) by smRNA-seq. Li teaches validation of the differential expression of 5′-tRFHis-GTG in a 237-specimen FFPE tissue cohort of localized and metastatic RCCs by RT-PCR. Li teaches that 5′-tRFHis-GTG has been found to be up-regulated in metastatic RCCs, comparing to the localized tumors in the 24-sample frozen tissue cohort. Validation test using a separate FFPE tissue cohort of 237 clinical specimens confirmed the upregulated 5′-tRFHis-GTG expression in metastatic RCC tissues. Li teaches that 5′-tRFHis-GTG, a novel tRNA-derived miRNA-like smRNA that is probably induced by oxidative stress, is upregulated in metastatic RCCs and involved in metastatic tumor cell proliferation and migration (abstract). Thus Li teaches a method comprising analyzing the levels of tRNAHisGTG fragment in a cell. It is noted that Li does not teach “wherein a differential in the measured tRNAHisGTG fragment levels compared to a reference is indicative of a diagnosis or identification of a breast cancer”. However this art rejection is set forth because it teaches a broad interpretation of the claims which does not require diagnosing or identifying breast cancer. Applicants are reminded that claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed.
Li does not teach hybridizing at least one tRNAHisGTG fragment obtained from a cell obtained from the subject to a panel of oligonucleotides engineered to detect the tRNAHisGTG (clm 14).
However Thompson teaches hybridizing at least one tRNAHisGTG fragment obtained from a cell obtained from the subject to a panel of oligonucleotides engineered to detect the tRNAHisGTG (page 2096, col 1, page 2102, col 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Li by hybridizing at least one tRNAHisGTG fragment obtained from a cell obtained from the subject to a panel of oligonucleotides engineered to detect the tRNAHisGTG as suggested by Thompson for the benefit of being able to detect the tRNAHisGTG fragment using hybridization since it was well known, routine, and conventional in the art to detect nucleic acid targets by hybridizing nucleic acid probes.
The combined references do not further teach providing a treatment regimen to the subject (clm 14).
However Hutson teaches that in recent years several targeted therapies have become available for first- and second-line use for metastatic renal cell carcinoma. These include sorafenib, sunitinib, bevacizumab (plus IFN-), temsirolimus, everolimus, and, most recently, pazopanib (abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Li and Thompson by further providing a treatment to subjects with a tRF signature for metastatic RCC as suggested by Hutson. One of skill in the art would have been motivated to provide a treatment comprising a targeted therapy since Hutson teaches that molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. Hutson further teaches that they have superior outcomes (abstract).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Li (Molecular and Cellular Biology AACR 104th Annual Meeting 2013; Apr 6-10, 2013) in view of Hutson (The Oncologist 2011; 16(suppl 2):14-22.
Regarding Claim 20 it is noted that MPEP 2111.02 states, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” In the present situation, the process steps are able to stand alone and the preamble limitation is not accorded patentable weight. Accordingly, the claim language of “A method of identifying a cells tissue of origin to treat and/or prevent a disease or condition, disease recurrence, or disease progression” merely sets forth the purpose of the process, but does not limit the scope of the claims.
Regarding Claim 20 Li teaches that they characterized 5′-tRFHis-GTG, a novel tRNA-derived novel miRNA-like smRNA, in renal cell carcinoma (RCC) metastasis. Li teaches that they examined 5′-tRFHis-GTG expression profiles in benign kidney tissue, localized and metastatic RCCs in a frozen tissue cohort (n=24) by smRNA-seq. Li teaches validation of the differential expression of 5′-tRFHis-GTG in a 237-specimen FFPE tissue cohort of localized and metastatic RCCs by RT-PCR. Li teaches that 5′-tRFHis-GTG has been found to be up-regulated in metastatic RCCs, comparing to the localized tumors in the 24-sample frozen tissue cohort. Validation test using a separate FFPE tissue cohort of 237 clinical specimens confirmed the upregulated 5′-tRFHis-GTG expression in metastatic RCC tissues. Li teaches that 5′-tRFHis-GTG, a novel tRNA-derived miRNA-like smRNA that is probably induced by oxidative stress, is upregulated in metastatic RCCs and involved in metastatic tumor cell proliferation and migration (abstract). Thus Li teaches a method comprising characterizing a tRNAHisGTG fragment and its relative abundance isolated from a sample obtained from the subject to identify a signature. It is noted that Li does not teach “wherein when the signature is indicative of the cells tissue of origin”. However this art rejection is set forth because it teaches a broad interpretation of the claims which does not require detecting the tissue of origin. Applicants are reminded that claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed.
Li does not teach further providing a treatment regimen to the subject (clm 20).
However Hutson teaches that in recent years several targeted therapies have become available for first- and second-line use for metastatic renal cell carcinoma. These include sorafenib, sunitinib, bevacizumab (plus IFN-), temsirolimus, everolimus, and, most recently, pazopanib (abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Li by further providing a treatment to subjects with a tRF signature for metastatic RCC as suggested by Hutson. One of skill in the art would have been motivated to provide a treatment comprising a targeted therapy since Hutson teaches that molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. Hutson further teaches that they have superior outcomes (abstract).
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Honda in view of Katibah (PNAS Aug 19, 2014 Vol 111 No 33 pages 12025-12030).
The teachings of Honda are presented above.
Honda does not teach a method wherein the tRNA-HIS(GTG) fragment is post-transcriptionally modified with at least one selected from the group consisting of guanylation, uridylation, adenylation, P, cP, OH, and aa (clm 6). Regarding claim 7, it is an inherent property of the HisGTG 5’ fragment that it interacts with ago.
However Katibah teaches that HisGTG is post transcriptionally modified with a 5’ guanosine addition (page 12029, col 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Honda by detecting HisGTG is post transcriptionally modified with a 5’ guanosine addition as suggested by Katibah. In particular Katibah teaches that this particular modification is expected. Thus it would have been obvious to include detecting tRNA-HIS(GTG) fragment that have been modified with guanylation since this appears to be an expected post transcriptional modification.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Honda in view of Thompson (RNA 2008 14:2095-2103).
The teachings of Honda are given previously in this Office action and are incorporated here.
Honda does not teach hybridizing at least one tRNAHisGTG fragment obtained from a cell obtained from the subject to a panel of oligonucleotides engineered to detect the tRNAHisGTG (clm 14).
However Thompson teaches hybridizing at least one tRNAHisGTG fragment obtained from a cell obtained from the subject to a panel of oligonucleotides engineered to detect the tRNAHisGTG (page 2096, col 1, page 2102, col 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Honda by hybridizing at least one tRNAHisGTG fragment obtained from a cell obtained from the subject to a panel of oligonucleotides engineered to detect the tRNAHisGTG as suggested by Thompson for the benefit of being able to detect the tRNAHisGTG fragment using hybridization since it was well known, routine, and conventional in the art to detect nucleic acid targets by hybridizing nucleic acid probes.
The combined references do not further teach providing a treatment regimen to the subject (clm 14).
However, treating a patient having breast cancer was well known at the time of the invention, the examiner takes Official notice.
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Honda and Thompson by further providing a treatment to subjects with a tRF signature for ER+ breast cancer. One of skill in the art would have been motivated to provide a treatment comprising a therapy since in order to ameliorate the disease.
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable Honda.
The teachings of Honda are given previously in this Office action and are fully incorporated here. These clearly meet the required method steps of claim 20 except Honda does not teach further providing a treatment regimen to the subject (clm 20).
However, treating a patient having breast cancer was well known at the time of the invention, the examiner takes Official notice.
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Honda and Thompson by further providing a treatment to subjects with a tRF signature for ER+ breast cancer. One of skill in the art would have been motivated to provide a treatment comprising a therapy since in order to ameliorate the disease.
Improper Markush Rejection
Claims 5 and 21 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 claims recite the following Markush grouping: at least one selected from the group consisting of SEQ ID NOs: 1-858.
The Markush groups 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 SEQ ID NO has a different chemical structure in that it consists of a different nucleotide sequence. The only structural similarity present is that all of the SEQ ID NOs comprise nucleotides. The fact that the SEQ ID NOs 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 diagnostic for ANY disease/condition. Accordingly, while the different SEQ ID NOs: are asserted to have the property of being diagnostic for ANY disease/condition or being correlated with a tissue of origin, they do not share a substantial structural similarity essential to this activity.
Further, the recited genes do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that genes 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 SEQ ID NOs: possess the common property of being diagnostic for ANY disease/condition or being correlated with a tissue of origin.
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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 4-7, 9, 11-14, 20-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/910568 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The copending claims anticipate claims 1-2, 4, 5, 6-7, 9, see claim 4 in the copending application noting that SEQ ID NO: 4976 in the copending application is identical to SEQ ID NO: 59.
While the copending claims do not state the sample is from a cell, tissue or body fluid obtained from the subject as required by copending claims 11 and 12, or one of the cells taught in claim 13, the specification which supports the copending claims defines biological sample as being any tissue or fluid giving as examples many which overlap with the samples in these claims. See copending specification p. 5, line 3 and following which defines “biological sample.”
Regarding claim 14, the copending claims teaches detecting the tRNA fragment by PCR (see copending claim 16) a method which includes hybridizing to a set of primers which is a panel of oligonucleotides engineered to detect the tRNA fragment. Regarding claims 14 and 20-21, the copending claims do not teach providing a treatment regimen to the subject. However, the copending claims each assessing that a person has or is at risk of developing melanoma, and it would have been prima facie obvious to have modified the copending claims to include providing a treatment regimen to the subject upon finding that the subject is indicated to have uveal melanoma to ameliorate the negative effects of the disease.
Regarding claim 22, while the copending claims do not state that the subject is a human, the part of the specification that supports the claims teaches at a patient is a human is encompassed within the claims, see copending application, p. 7, line 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached on (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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