DETAILED ACTION
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 the species of genes that are increased and decreased in claim 120, and a species of sample prior to treatment, in the reply filed on 3/2/26, is acknowledged. Claims 116-119, 122-125 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to non-elected species.
Claims 112, 120-121, and 126 are being acted upon.
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 112, 120-121, and 126 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature without significantly more. The claim(s) recite(s) a correlation between interferon inducible gene expression profiles and identification as a patient having Sjogren’s syndrome that candidates for treatment. This judicial exception is not integrated into a practical application because said correlation between Sjogren’s syndrome and said expression profiles are laws of nature. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
Laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. The courts have often described these exceptions using other terms, including “physical phenomena,” “scientific principles”, “natural laws,” and “products of nature.” Product of nature exceptions include both naturally occurring products and non-naturally occurring products that lack markedly different characteristics from any naturally occurring counterpart. See, e.g.,Ambry Genetics, 774 F.3d at 760, 113 USPQ2d at 1244 (“Contrary to Myriad's argument, it makes no difference that the identified gene sequences are synthetically replicated. As the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible.”). Thus, a synthetic, artificial, or non-naturally occurring product such as a cloned organism or a human-made hybrid plant is not automatically eligible because it was created by human ingenuity or intervention. See, e.g.,In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1337, 110 USPQ2d 1668, 1671-72 (Fed. Cir. 2014) (cloned sheep); cf. J.E.M. Ag Supply, Inc. v. Pioneer Hi-Bred Int’l, Inc., 534 U.S. 130-132, 60 USPQ2d 1868-69 (2001) (hybrid plant). Instead, the key to the eligibility of all non-naturally occurring products is whether they possess markedly different characteristics from any naturally occurring counterpart. See MPEP 2106.04(b).
The instant claims set forth laws of nature- namely relationships between interferon gene expression profiles and having Sjogren’s syndrome that is treatable by a candidate treatment. The claims are directed to a process, as set forth in Step 1 of the subject matter eligibility test (see MPEP 2106). Regarding step2A, prong 1, the claim recites a judicial exception, a law of nature, as noted above. Regarding step 2A, prong 2, the claims do not recite any additional elements that integrate the judicial exception into a practical application, such as elements that improve the functioning of a computer or other technology, or applying the judicial exception to effect a particular treatment or prophylaxis of disease. For example, the present claims do not require actually treating a patient with a an RNAse nuclease agent, but rather only requires measuring levels certain biomarkers to identify a patient as a candidate for treatment with the RNA nuclease agent. Regarding step 2B, the claims do not recite additional elements that amount to significantly more than the judicial exception. The step of determining interferon-inducible gene expression profiles using gene arrays (including those within the scope of claim 120) in a sample obtained from a patient, consist of well understood, routine, conventional activity already engaged in by the scientific community. See, for example, Hjelmervik, 2005, Nguyen, Nezos, 2015 (of record), Mavragani, Gottenberg, 2006 and WO2012/149440. The comparison step is also routine, and is itself a judicial exception (mental process). Additionally, the steps are recited at a high level of generality and do not impose a meaningful limit on the scope of the claim. Moreover, when the claim is considered as a whole, the steps taken together amount to no more than recognizing the law of nature itself. The Court has made clear that to transform an unpatentable law of nature into a patent-eligible application of such a law, one must do more than simply state the law of nature while adding the words "apply it." Essentially, appending conventional steps specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patent-eligible.
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
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 120-121 and 126 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.
Claim 120 is indefinite in that it recites that the interferon-inducible gene expression profile comprises an increase and a decrease in expression of one or more “inflammatory-related genes”. It is unclear if the inflammatory related genes are species of interferon-inducible genes recited in claim 1112, or whether they represent a distinct group of gene expression levels that are determined in addition to interferon inducible genes recited in claim 112. In other words, would claim 120 encompass a gene expression profile based only one or more of the increased and decreased inflammatory genes listed, i.e. an increased in CD36 and a decrease in NUPR1, for example. Or do the claims require also determining interferon inducible gene expression profiles, in addition to the inflammatory genes recited in claims 120. The scope of the claims is unclear and indefinite.
Claims 121 and 126 are indefinite, since it is unclear how the method can be a method for selecting a candidate patient for treatment, when the controls sample that is used for comparison to the candidate patient sample is a sample form the patient prior to treatment. In other words, samples from candidate patients that are to be identifying would already be undergoing treatment with the nuclease agent, since they are to be compared to a control sample from the patient prior to treatment with the nuclease agent. It is unclear how this can be considered a method of identifying a patient with Sjogren’s syndrome as a “candidate” for treatment with a nuclease agent, if the patient is already being treated with the nuclease agent. Are the claims meant to encompass a method of monitoring a patient undergoing treatment, wherein levels are compared before and after treatment, i.e. the method identifies responder or non-responder patients? The scope of the claims is unclear and indefinite. For the purposes of examination, the claim is being interpreted as encompassing monitoring treatment efficacy in a treated patient.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 120 and 126 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The specification and the claims as originally filed do not provide support for the invention as now claimed, specifically:
A method of identifying a patient having Sjogren’s syndrome as a candidate for treatment with an RNA nuclease agent, wherein the interferon induce gene profile comprises an increase of the inflammatory related genes recited in claim 120 part (1) , as compared to a suitable control; and a decrease in the inflammatory related genes recite in claim 120 part (2), as compared to a suitable control of claim 120 (Claim 120, and dependent claims 126).
A review of the specification fails to reveal support for the new limitations.
The specification discloses the method of identifying a patient having Sjogren’s syndrome as a candidate for treatment with an RNA nuclease agent comprising determining interferon inducible gene expression profiles from the patient and comparing the profile with a suitable control, wherein the interferon-inducible gene expression profile indicates the patient is a candidate for treatment (i.e. the method of claim 112). The specification on pages 141-142 also disclosed identifying a patient based on determining inflammatory gene expression profiles and further discloses that the inflammatory related genes include those recited in (1) and (2) of instant claim 120. However, the specification does not disclose a method of identifying a candidate patient for treatment wherein the expression profile comprises an increase in the genes of (1) and a decrease in the genes in (2) as compared to the suitable control, as recited in claim 120.
The specification on page 140-141 discloses a method of treating Sjogren’s disease with a RNA nuclease agent, wherein the treatment results in an increase in the genes recited in instant claim 120 (1) and a decrease in the genes recited in claim 120 (2). However, this does not provide support for the claimed patient identification method which has a different scope than a treatment method involving monitoring gene expression proles after treatment. For example, the present claims encompass comparing a sample from a candidate patient prior to treatment, to that of a healthy control, wherein an increase in CD36 and a decrease in NUPR1, as compared to the healthy control, identify the patient as a candidate for treatment. However, the specification discloses that effective treatment with the claimed RNA nuclease agent results in an increase in CD36 and a decrease in NUPR1. In other words, selecting a patient with (already) increased CD36 and decreased NUPR1 as a candidate for treatment with a RNA nuclease whose mechanisms of action increases CD36 and decreases NUPR1 was not contemplated in the specification. See MPEP 2163, newly added claims or claim limitations must be supported in the specification through express, implicit, or inherent disclosure. The specification did not contemplate the method of identifying a patient claim 120 as broadly claimed, wherein patients for treatment are selected on the basis of the increased and decreased listed genes compared to a suitable control. At best, the specification would support monitoring an RNAse nuclease agent treated subject by measuring said increase or decreased expression levels of the genes in claim 120 before and after treatment.
Claims 112, 120-121, and 126 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 specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, see In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” “The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling” (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. With these teachings in mind, an enabling disclosure, commensurate in scope with the breadth of the claimed invention, is required.
The instant claims are directed to a method of identifying a patient having Sjogren's syndrome as a candidate for treatment with an RNA nuclease agent comprising (a) determining an interferon-inducible gene expression profile in a sample obtained from the patient; and (b) comparing the interferon-inducible gene expression profile determined in step (a) with an interferon-inducible gene expression profile in a sample obtained from a suitable control subject; and wherein the interferon-inducible gene expression profile indicates the patient is a candidate for treatment with an RNA nuclease agent. The claims broadly encompass a genus of different controls, and wherein the comparison could be an increase and/or a decrease in a large genus of distinct interferon inducible genes. The state of the art is such that Sjogren’s syndrome is characterized by activation of type I interferon pathway, and certain genes activated in response to type I interferon are elevated in Sjogren’s’ syndrome as compared to healthy controls (see Mavragani, 2010). RNA nucleases such as RSLV-132 (i.e. a homodimer of SEQ ID NO: 50) can be used to treat Sjogren’s syndrome and function to reduce production of type 1 interferon (See Fisher, 2019, of record). Therefore, based on the state of the art, one could select a Sjogren’s patient for treatment with an RNA nuclease, wherein the patient has increased levels of, for example, type 1 interferon inducible genes as compared to a healthy control, and wherein the treatment with the RNA nuclease would lower the aberrant type 1 interferon genes to treat the subject. However, the present claims are not limited to such a method and broadly encompass, for example, selecting a subject based on a decreased level of type 1 interferon responsive genes as compared to a healthy control. The instant claims are also not limited to type 1 interferon and would encompass a genus of other interferon inducible genes, for example, type 2 or type 3 interferon inducible genes. Furthermore, the claims encompass healthy control subjects, non-responder subjects, or even the subject to be selected, wherein the comparison is to the levels in the subject prior to treatment.
Regarding claims 120 and 126, the claims specify certain inflammatory gene combinations that are increased and decreased relative to the control. The claims encompass a large genus of different gene profile including any one or more of the genes in part (1) being increased, and one or more of genes in part (2) being decreased. The claims encompass a genus of control subjects as the basis of comparison, including the patient prior to treatment, a non-responder patient, or a healthy subject. The instant specification discloses that the genes in part (1) of claim 120 are increased in RNAse agent treated subjects as compared to the subjects prior to treatment, and that the expression of genes in part (2) are decreased in RNAase treated subjects as compared to the subject prior to treatment. In other words, the subject prior to treatment had increased levels of the gene expression of the genes in (2), and decreased expression levels of the genes in (1), which were decreased and increased after treatment, respectively. However, the present claims encompass identifying a subject as being suitable for treatment when the genes in (1) exhibit increased expression as compared to, for example, a healthy control, and the genes in (2) exhibit a decreases as compared to a health control. Identifying such a patient as suitable for treatment would be highly unpredictable, since the specification explicitly teaches that the mechanism of action of the claimed nuclease involved increasing expression of the genes in (1) and decreasing expression of the genes in (2). In other words, the claims would encompass identifying a subject as suitable for treatment wherein the genes in (2) are already decreased, and it would be highly unpredictable that a treatment that relies on decreasing expression of said genes (as disclosed), could function to treat disease.
Given the unpredictably of the art and the breadth of the claims, the instant specification must provide a sufficient and enabling disclosure commensurate in scope with the instant claims. The instant specification discloses that certain specific interferon inducible or inflammatory genes are increased or decreased after treatment with RSLV-132, as compared to prior to treatment, in patients that achieve a clinical response. However, this is not commensurate in scope with the instant claims, which are not directed to monitoring treatment efficacy in treated patients, but rather encompass identifying a patient as a candidate for treatment. The claims encompass a genus of controls as the basis for comparison, i.e. healthy controls and a wide genus of distinct genes that can be both increased and decreased in any combination. The specification does not provide sufficient guidance to practice the method as broadly claimed. For example, no guidance is provided regarding which genes and in which combinations should be increased or decreased when identifying a patient as a suitable candidate for treatment as compared to, for example, a healthy control. Given the unpredictably of the art, the breadth of the claims, and the lack of guidance provided by the instant specification, it would require undue experimentation to practice the full scope of the claimed method.
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.
Claims 112 and 121 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fisher, June 13, 2019, in view of WO2012/149440 (both of record).
Fisher teaches a method of identifying a patient having Sjogren’s syndrome as a candidate for treatment with an RNA nuclease agent RSV-132 (said RSV-132 is inherently is a homodimer of two polypeptides of SEQ I DNO: 50), wherein the method comprises determining that the patients have a positive type I interferon inducible gene expression profile.
The reference differs from the claimed invention in that it does not explicitly teach that the increase in the positive type I interferon gene profiled is determined by comparison with a sample from a suitable control, it would be obvious that determining positive profile would require comparison to a control. The ordinary artisan would be motivated to include a sample from a suitable control subject to ensure that the positive levels detected were accurate and for quality control in the assay.
Regarding claim 121, Fisher also does not explicitly teach comparison to a control that is a sample from the patient prior to treatment.
WO2012/149440 teaches that RNAase nuclease therapy therapy effectiveness can be monitored by measuring and comparing type I IFN response gene levels prior to and after therapy, wherein the number and strength of doses are adjusted according to the subjects needs (see paragraphs 335-340, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to compare the type I IFN gene expression levels in the treated patient and compare to the levels in the patient prior to treatment in order to monitor the effectiveness of the treatment to adjust the number and strength of the dose according to the subject’s needs, as taught by WO2012/149440. For example, if the type I IFN genes were found to be decreased in the treated subject, as compared to a sample from prior to treatment (i.e. control) one would conclude that the treatment dose was effective and continue treating the subject with the RNAase agent. This would be within the scope of the claimed method of identifying a candidate patient for treatment.
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 112, 1201-121, and 126 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-72, 84-104 of copending Application No. 19/327,472 in view of Fisher, June 13, 2019 and WO2012/149440.
Claims 91-92 of the ‘472 application are directed to a method of identifying a patient having Sjogren’s syndrome as a candidate for treatment with an RNA nuclease agent comprising determining an inflammatory related gene expression profile and comparing to a sample obtained from a suitable control, wherein the inflammatory related genes are selected from STAT1 and STAT2, i.e. an interferon-inducible gene expression profile. Although claims 91-92 are not limited to an RNA nuclease agent of SEQ ID NO; 50 (i.e. RSLV-132), it would be obvious to use RSLV-132, since Fisher teaches it is effective for treating Sjogren’s syndrome. Furthermore, the claims of the ‘472 application, for example, claim 1 and 12, are also directed to treating a patient with Sjogren’s’ disease comprising administering the same RNase agent comprising SEQ ID NO: 50 as the present claims. Selecting a patient for treatment and monitoring the patient by determining type I interferon gene expression would be obvious based on the teachings of Fisher and WO 2012/149440 for the same reasons set forth above.
Regarding claims 120 and 126, the ‘472 application claims a method of treating Sjogren’s disease comprising administering an RNAse nuclease agent, wherein the treatment increases one or more inflammatory genes, such as CD163 (see, for example, claim 88) and decreases one ore more inflammatory genes, such as IL-5 (see, for example, claim 85). It would be obvious to monitor treatment as taught by WO 2012/149440, by measuring said genes before and after treatment in order to effectively treat the subject for the same reasons set forth above. For example, one could determine that CD163 is increased in the treated patient and IL-5 is decreased as meaning that the treatment is effective and continuing the treatment (i.e. “identifying a patient).
This is a provisional nonstatutory double patenting rejection.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644