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 .
Election/Restrictions
Applicant’s election of Group I and the election of the combination of tie1 ndufa4l2 esm1 flt4 kdr flt1 enpep cd34 cdh6 dll4 vegfa sema5b angptl4 tek angpt2 in the reply filed on 6/20/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-3, 5-9, 11-12, 14, 16-19, 21, 23-25, 27-28, 30 and 32-40 are pending.
Claims 4, 10, 13, 15, 20, 22, 26, 29 and 31 are cancelled.
Claims 12, 14, 16-19, 21, 23-25, 27-28, 30, 32, 37-40 are withdrawn as being drawn to nonelected inventions.
An action on the merits for claims 1-3, 5-9, 11, 33-36 is set forth below.
Claim Objections
Claims 1-3, 5-9, 11, 33-36 are objected to because of the following informalities: The gene names in claim 1 should be spelled out with the abbreviation in parentheses for clarity. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 5-9, 11, 33-36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for,
A method for predicting if a human subject with melanoma will respond to treatment with a PD-1 antagonist comprising:
(a) obtaining a melanoma sample from a human patient;
(b) measuring the raw RNA expression levels of tie1 ndufa4l2 esm1 flt4 kdr flt1 enpep cd34 cdh6 dll4 vegfa sema5b angptl4 tek angpt2in the melanoma sample;
(c) normalizing the raw RNA expression levels;
(d) calculating the arithmetic mean of the normalized RNA expression levels to generate a score; and
(e) predicting that the human subject with melanoma will respond to treatment with a PD-1 if the score calculated in step (d) is higher than a reference score or predicting that the human subject with melanoma will not respond to treatment with a PD-1 if the score calculated in step (d) is lower than a reference score.
does not reasonably provide enablement for the methods as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention
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)).
Scope of the Claims
The claims are drawn to methods for testing a tumor for the presence or absence of a biomarker that predicts response to treatment with a PD-1 antagonist by measuring the expression level of each gene in a gene signature.
In view of the recitation of the term “tumor” the claims encompass any type of tumor including both benign tumors and malignant tumors. The malignant tumors can be ANY type of cancerous tumor (breast, lung, pancreatic, melanoma, prostate etc.).
Teachings in the Specification and Examples
The specification (Examples 1-2) teaches that the inventors investigated whether a gene expression signature could be derived that would be useful in predicting which patients are more likely to have an anti-tumor response to therapy with a PD-1 antagonist. The inventors discovered that 99 genes were associated with a better response to treatment (see Table 1) in a treatment with PD-1 antagonist with a patient with angiogenesis. Next the inventors hypothesized that gene signature biomarkers, which would provide a clinically relevant cutoff point for predicting response antiPD-1, could be generated from the genes in Table 1 (example 1). A gene signature for angiogenesis genes was determined in table 6, which are the combination of 10 genes in claim 1. However, the specification does not provide prediction of treatment response based upon any presence or absences of biomarkers in any cancer tumor sample from any species.
State of the Art and the Unpredictability of the Art
The art of determining an association between a gene signature and the occurrence of a phenotype, such as response to a PD-1 antagonist, is highly unpredictable.
Further, the art, as recited below, teaches that expression of biomarkers differ in different species. However, the specification has not provided identifying characteristics or functional attributes that would distinguish different members of the claimed genus. Rather, the art teaches that changes in the structure of nucleic acids between species can have an effect on expression. Enard et al. (Science 2002 Vol 296 p. 340) teaches that even between closely related species gene expression patterns differ (abstract). Enard et al. teaches that mRNA expression levels are different between humans, chimpanzees, orangutans and rhesus marcques (p. 340 1st column last sentence-2nd column 1st paragraph). Enard et al. teaches that there are a large number of quantitative differences in gene expression in closely related mammals (p. 342 2nd column last paragraph).
The art of Cobb et al (Crit Care Med 2002 Vol. 30 p. 2711) teaches the in analysis of gene expression in spleen and liver sample from septic mice. Notably, the reference teaches that, when compared to a non-septic sample, the relevant expression profiles of the septic mouse spleen and the septic mouse liver contain different nucleic acids at different levels (Table 1; p.2714, middle col., lns.2-8). As such the art teaches that expression levels of the same nucleic acids in different tissue samples differ. Therefore the art indicates that the identifying characteristics or functional attributes that would distinguish different members of the claimed genus will differ depending on the sample type. The teachings in the specification do not provide enablement for a method of predicting the response that ANY tumor type will have to treatment with a PD-1 antagonist. The specification (Example 2) discloses a gene signature comprising of tie1 ndufa4l2 esm1 flt4 kdr flt1 enpep cd34 cdh6 dll4 vegfa sema5b angptl4 tek angpt2that can be used to predict whether melanoma patients will respond to treatment with a PD-1 antagonist. However there is no data in the specification on the expression level of these genes in other tumor samples derived from patients that have been treated with PD-1 antagonists. The tumor types encompassed by the claims are expected to have different expression patterns and different responses to treatment with PD-1 antagonists. It is noted that the analysis in the specification was limited to melanoma tumors. While the specification discloses genes expressed in melanoma tumors that are predictive of response to treatment with a PD-1 antagonist, there is no evidence in the specification that these same genes in other types of tumors will also be predictive of response to treatment with a PD-1 antagonist. Thus the specification does not provide enablement for a method of being able to predict the response that ANY tumor will have to treatment with a PD-1 antagonist.
Quantity of Experimentation:
For the reasons discussed above, it would have required undue, unpredictableexperimentation of a trial- and-error nature to practice the recited methods in the full, broad scope encompassed by the rejected claims. The type of experimentation requiredis not routine and the subsequent data analysis is sophisticated. Furthermore, theoutcome of the tasks is entirely unpredictable based on the limited data and analysisprovided in the instant specification.Conclusions:
Taking into consideration the factors outlined above, including the nature of theinvention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue amount of experimentation would be required to make and use the invention.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 56, 11, 33-36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1-3, 5-6, 11, 33-36 are indefinite over step f. The preamble is drawn to testing a tumor for the presence or absence of a biomarker, however, the classification is based upon gene signature score. This gene signature score is based upon the expression of a group of 10 genes which does not provide for the “presence or absence of a biomarker”. Therefore the metes and bounds of the claims are unclear.
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 1-3, 5-9, 11, 33-36 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Note that the unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012).
The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014).
Applicant’s attention is also directed to University of Utah Res. Foundation v. Ambry Genetics Corp. No. 2014-1361, -1366 (Fed. Cir. Dec 17, 2014). Therein, the Court stated:
Recently in Alice the Supreme Court reiterated its two-step test to determine patent eligibility for any claims that allegedly encompass abstract ideas. First, “we determine whether the claims at issue are directed to [a] patent-ineligible concept[].If so, we then ask, ‘what else is there in the claims before us?’” Id. at 2355 (quoting Mayo, 132 S. Ct. at 1296–97) (citations and punctuation omitted). That is, we next ask whether the remaining elements, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to “transform the nature of the claim’ into a patent-eligible application.” Id. at 2355 (quoting Mayo, 132 S. Ct. at 1297). Put another way, there must be a further “inventive concept” to take the claim into the realm of patent eligibility. Id. at 2355.
The instant claims are directed to laws of nature. The claims are based on a correlation between the expression level of tie1 ndufa4l2 esm1 flt4 kdr flt1 enpep cd34 cdh6 dll4 vegfa sema5b angptl4 tek angpt2and the response to treatment with a PD-1 antagonist. 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.
Additionally the instant claims are directed to abstract ideas. The claims recite the following limitations:
-normalizing raw RNA expression levels (clms 1 and 7);
-calculating the arithmetic mean of the normalized RNA expression levels to generate a score for the gene signature (clms 1 and 7)
-comparing the calculated score to a reference score for the gene signature;
-classifying the tumor as biomarker positive or biomarker negative; and
-determining if the tumor is positive or negative for a PD-L1 gene signature biomarker
Here the steps of “normalizing” and “calculating” broadly encompass methods of abstract data manipulation and analysis. The “comparing” step broadly encompasses a step that may be accomplished mentally by looking at two different scores. The “classifying” step broadly encompasses a step that may be accomplished mentally by thinking about the score. The “determining” step broadly encompasses a step that may be accomplished mentally by reading a patient’s medical chart indicating if they are positive or negative for a PD-L1 gene signature biomarker. These steps could be performed by a human using mental steps or basic critical thinking, which are the types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics or the diagnosing an abnormal condition by performing clinical tests and then thinking about the results in Grams).
Applicant’s attention is directed to the Association for Molecular Pathology (AMP) and ACLU v. USPTO and Myriad Genetics (Fed. Cir. 2012)) wherein it is stated at 56-57:
We renew our conclusion that Myriad’s claims to “comparing” or “analyzing” two gene sequences fall out-side the scope of § 101 because they claim only abstract mental processes. See Benson, 409 U.S. at 67 (“Phenomena of nature, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.”). The claims recite, for example, a “method for screening a tumor sample,” by “comparing” a first BRCA1 sequence from a tumor sample and a second BRCA1 sequence from a non-tumor sample, wherein a difference in sequence indicates an alteration in the tumor sample. ’001 patent claim 1. This claim thus recites nothing more than the abstract mental steps necessary to compare two different nucleotide sequences: one looks at the first position in a first sequence; determines the nucleotide sequence at that first position; looks at the first position in a second sequence; determines the nucleotide sequence at that first position; determines if the nucleotide at the first position in the first sequence and the first position in the second sequence are the same or different, wherein the latter indicates an alteration; and repeats the process for the next position.
Additionally, in University of Utah Res. Foundation v. Ambry Genetics Corp.(Fed Cir, 2014), the Court held that:
Having determined that the comparison steps of claims 7 and 8 are abstract ideas, we move to the second step of Alice and ask whether the particular mechanism for the comparisons added by claims 7 or 8 renders the claims patent-eligible. For this step, Alice dictates that we ask whether the remaining elements, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to “‘transform the nature of the claim’ into a patent-eligible application.” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297). There must be a further inventive concept to take the claim into the realm of patent-eligibility. Id. at 2355. The second paragraph of claim 7 describes the way in which the sequences are compared: they are compared by 1) hybridizing a BRCA gene probe and 2) detecting the presence of a hybridization product. Similarly, claim 8 requires 1) amplification of the BRCA1 gene and 2) sequencing of the amplified nucleic acids. The non-patent-ineligible elements of claims 7 and 8 do not add “enough” to make the claims as a whole patent- eligible.
Thereby, having determined that the claims involve judicial exceptions, it is then determined whether the remaining elements, either in isolation or combination with the other non-patent-ineligible elements, are sufficient to “transform the nature of the claim” into a patent-eligible application.
In addition to the judicial exceptions the claims recite the following steps
- obtaining a sample from a tumor (clms 1, 7)
-measuring the raw RNA expression level in the tumor sample (clms 1, 7);
-administering a PD-1 antagonist if the tumor is positive for a biomarker (clms 5,7);
-administering a cancer treatment that does not include a PD-1 antagonist if the tumor is negative for the biomarker (clms 5,7);
-sending the tumor sample to a laboratory with a request to test the sample (clm 4); and
-receiving a report for a laboratory that states whether the tumor is negative or positive for a biomarker (clm 4).
Here the steps of obtaining a sample in order to perform a test are well understood, routine, and conventional activity for those in the field of diagnostics. The “measuring” steps are recited at a high level of generality such that they amount to insignificant presolution activity, e.g., mere data gathering. The claims merely instruct a scientist to use any method of measuring gene expression levels and the claims do not require the use of any particular reagents (i.e., primers, probes, etc.). When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention and at the time the application was filed.
Additionally it is relevant to note that the prior art of Mule (US Patent Application 2013/0034540 Feb 7, 2013) teaches a method for treating a subject who has a tumor by obtaining cells from the tumor, determining expression levels in the tumor sample and then selecting for the subject a treatment comprising an immunotherapy if tumor gene expression levels are above reference gene expression levels or selecting for the subject a treatment not comprising an immunotherapy if tumor gene expression levels are below the reference gene expression levels (page 3, lines 4-24). Additionally Mule teaches that the immunotherapy is an anti PD1 antibody (page 5, lines 8-12). Thus the additionally recited steps of “obtaining” “measuring”, and “administering” when considered alone or in combination do NOT add significantly more to the judicial exceptions.
Further it is noted that the steps of “sending” a tumor sample to a laboratory with a request to perform a test and then “receiving” a report on the test that was performed do not amount to significantly more. Sending a sample to a laboratory with instructions to perform a test is well understood, routine, and conventional activity for those in the field of diagnostics.
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/ Primary Examiner, Art Unit 1682