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 .
Status of Claims
Claims 3, 6, 11, 13-20, 28-53, 56-57, 59, 61-63, and 67-91 are cancelled.
Claims 1-2, 4-5, 7-10, 12, 21-27, 54-55, 58, 60, and 64-66 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
No information disclosure statement has been submitted to date.
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.
Claim 54 is 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 claim 54, the phrase "e.g.," renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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, 4-5, 7-10, 12, and 21-27 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.
Adequate written description support for a claimed genus may be provided by describing sufficient identifying characteristics, describing a representative number of species, actual reduction to practice, disclosure of drawings or structural chemical formulas, complete or partial structure, physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure and any working examples, method of making the claimed invention, level of skill and knowledge in the art as well as predictability in the art are other determinants that are used to analyze whether applicants had possession of the claimed genus. The present specification fails to meet these requirements for the following reasons.
Biomarker genus
Claims 1 and 2 broadly recite “a biomarker” without limiting the biomarker to a particular tissue, biological process, disease state, or class of biomarkers associated with AHP. Thus, the claims encompass biomarkers associated with substantially any biological tissue or physiological process, provided that the biomarker has an elevated level relative to a reference level.
The specification, however, does not describe this broad genus. Rather, the specification describes the use of renal-injury biomarkers in subjects with AHP and identifies KIM1, APLP1, MMP7, NGAL, CST3, and CHI3L1 as particular biomarkers that may be measured to identify or monitor AHP ([0004]-[0008], Example 2). The specification does not identify a common structural, biochemical, or functional characteristic shared by these disclosed biomarkers and the full genus of biomarkers encompassed by claims 1 and 2. Nor does it disclose a correlation that would allow a person of ordinary skill in the art to identify other biomarkers, including biomarkers associated with other tissues or biological processes, that would be indicative of AHP or whose elevated level would provide a basis for administering an ALAS1 inhibitor.
For example, the claims encompass a biomarker associated with pulmonary, cardiac, neurologic, hepatic, inflammatory, or other tissue injury, even though the specification provides no disclosure demonstrating that such a biomarker is associated with AHP or that an elevated level of such biomarker would indicate that administration of an ALAS1 inhibitor is appropriate. The specification therefore does not provide a representative number of species across the full scope of the claimed biomarker genus or otherwise provide sufficient identifying characteristics to demonstrate possession of the genus.
Moreover, the state of the art demonstrates that even the narrower class of renal-injury biomarkers disclosed in the specification is not a homogeneous class having predictable functional characteristics. For example, the prior art describes renal-injury biomarkers having different biological origins and mechanisms and reports that their diagnostic performance varies depending on the underlying disease and clinical circumstances (Abstract: Wen Y, Parikh CR. Current concepts and advances in biomarkers of acute kidney injury. Crit Rev Clin Lab Sci. 2021 Aug;58(5):354-368). Thus, disclosure of six particular renal-injury biomarkers does not establish possession of the substantially broader genus of any biomarker recited in claims 1 and 2.
ALAS1 therapeutic-agent genus
Claims 1 and 2 further broadly recite “a therapeutic agent that reduces expression of ALAS1” without limiting the therapeutic agent to a particular chemical structure, therapeutic class, mechanism of action, or sequence.
The specification describes ALAS1-lowering therapies including RNAi agents, antisense oligonucleotides, and specifically givosiran ([0009]). The specification does not, however, identify structural or functional characteristics common to the full genus of agents capable of reducing ALAS1 expression, nor does it provide a representative number of species spanning the breadth of the claimed genus.
The breadth of this genus is significant because agents capable of reducing expression of a gene may encompass structurally and mechanistically distinct therapeutic classes. The prior art recognizes, that siRNA and antisense oligonucleotide therapeutics employ different molecular structures, chemical modifications, mechanisms of action, and delivery requirements then, for example, small molecule inhibitors or biologics (Figure 1: Katzmann JL, et al., Targeting RNA With Antisense Oligonucleotides and Small Interfering RNA: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Aug 4;76(5):563-579). Accordingly, disclosure of the particular RNAi and antisense embodiments, including givosiran, does not identify a common structural or functional characteristic from which a person of ordinary skill in the art could reasonably identify other, undisclosed agents that would reduce ALAS1 expression and perform the claimed function.
Thus, the specification does not provide a representative number of species, structural characteristics, or a sufficient structure-function correlation demonstrating possession of the full genus of any therapeutic agent that reduces expression of ALAS1.
Dependent claims
Although claims 4-5 recite particular members of the biomarker genus, claims 4-5 remain deficient with respect to the therapeutic-agent genus because each depends from claim 2 and therefore encompasses any therapeutic agent that reduces expression of ALAS1.
Likewise, although claims 7-9 recite particular classes or species of ALAS1-lowering therapeutic agents, claims 7-9 remain deficient with respect to the biomarker genus because they ultimately depend from claim 2 and therefore encompass any biomarker. Claim 7, which broadly recites a nucleic acid therapeutic, is also deficient to the extent it encompasses nucleic acid therapeutics beyond the particular RNAi and antisense embodiments described in the specification.
Claims 10, 12, and 21-27 likewise depend, directly or indirectly, from claims 1 or 2 and therefore encompass the unsupported breadth of the biomarker and/or ALAS1 therapeutic-agent genera described above.
Accordingly, the specification, viewed as of the filing date and in light of the knowledge and predictability of the art, does not reasonably convey to a person of ordinary skill in the art that the inventors were in possession of the full scope of the biomarker and ALAS1 therapeutic-agent genera recited in claims 1 and 2.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 7-10, 12, 21-24, and 26-27, are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Querbes W, et al., (WO2017048843A1).
Regarding claim 1, Querbes teaches methods for treating a human subject having acute hepatic porphyria (AHP) by administering an inhibitor of 5'-aminolevulinic acid synthase 1 (ALAS1), thereby treating the subject, see claims 1 and 34, pg. 4 lines 23-28, pg. 11 lines 24-29, pg. 12 lines 22-28, pg. 14 lines 4-7, pg. 164 table 4, and pg. 33 lines 24-27. Querbes further teaches administering the ALAS1 after determining that the subject has an elevated level of a biomarker, see pgs. 235-241 Examples 39-40 Exemplary Clinical Studies, Key Eligibility Criteria and Results: Demographics and Baseline Disease Characteristics, and pg. 167.
Regarding claims 2, 10, 12, 21-24, and 26-27, Querbes teaches methods for treating a human subject having, or at risk of having acute hepatic porphyria (AHP) by obtaining a sample from a human subject, determining if the human subject has an elevated level of a biomarker and administering to the human subject an ALAS1 inhibitor, thereby treating the human subject. Querbes further teaches that the subject are asymptomatic high excreters (ASHE) (patients who have elevated levels of ALA and/or PBG, which are biomarkers of AHP). Querbes further teaches that the reference value is a healthy control level or when the subject is not in a disease state. Querbes further teaches that the level of the biomarker is increased by at least 2-fold, compared to the reference level of the biomarker. Querbes further teaches that the level is determined in a subject sample selected from blood, plasma, serum, urine, or stool. Querbes further teaches that the subject has not been diagnosed but is at risk of developing a porphyria or is suffering from one or more symptoms associated with AHP. Querbes further teaches that the subject may be treated with a second therapeutic agent and that the second agent may be a heme product, glucose, dextrose. For the above teachings, see claims 1, 29-31, and 33, pg. 58 lines 18-23, pg. 61 lines 15-17, pg. 163 lines 29-31, pg. 164 table 4, pg. 167 lines 1-31, pg. 168 lines 3-7 and 26-30, and pg. 171 lines 9-13, Pg 172 lines 10-29, pg. 173 lines 27-31, pg. 178 lines 18-22, and pgs. 235-241 Examples 38-40.
Regarding claims 7-9, Querbes teaches that the therapeutic agent that reduces the expression of ALAS 1 is a nucleic acid therapeutic, specifically an RNAi agent that has 100% identical nucleic acid sequence as givosiran, see claim 1 and SEQ ID NOs: 4153 and 4154.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-5, 7-10, 12, 21-24 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Querbes W, et al., (WO2017048843A1) as applied to claim 2 above in view of Pallet N, et al., (Kidney Int. 2015 Aug;88(2):386-95).
The teachings of Querbes are incorporated herein by reference to the 102 rejection above.
Querbes does not teach the biomarker is a renal injury biomarker and that the biomarker is selected from the group consisting of KIM1, APLP1, MMP7, NGAL, CST3, and CHI3L1.
Although Querbes does not teach the claimed renal injury biomarkers, Pallet teaches NGAL, which is one of the biomarkers recited in the alternative in claim 4. Pallet teaches that “the urinary concentrations of neutrophil gelatinase-associated lipocalin” (NGAL), “a marker of tubular damage, measured in acute intermittent porphyria (AIP) patients during crisis were higher compared with those in asymptomatic carriers, indicating that acute production of ALA and PBG may promote tubular injury,” see pg. 388 column 1. Pallet further teaches “an important issue that remains to be resolved is the timing with which renal injuries occur during AIP,” see discussion.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to employ the renal injury biomarker, NGAL, in the methods of Querbes. A PHOSITA would have been motivated because employing NGAL would have provided a readily measurable indicator of renal tubular injury associated with AHP, thereby facilitating identification and monitoring of subjects experiencing or at risk of renal injury and enabling treatment to be administered based on an objective measure of disease status. A PHOSITA would have had a reasonable expectation of success because NGAL was an established marker of tubular injury, and Pallet expressly demonstrated increased urinary NGAL in AIP patients during crisis; thus, a PHOSITA would have reasonably expected that measuring NGAL in the methods of Querbes would provide a detectable indication of AHP-associated renal injury.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Querbes W, et al., (WO2017048843A1) in view of Pallet N, et al., (Kidney Int. 2015 Aug;88(2):386-95) as applied to claims 1-2, 4-5, 7-10, 12, and 21-27 above, and further in view of Sardh E, et al., (N Engl J Med. 2019 Feb 7;380(6):549-558) and Balwani M, et al., (N Engl J Med. 2020 Jun 11;382(24):2289-2301).
The teachings of Querbes and Pallet are incorporated herein by reference to the preceding 102 and 103 rejections.
Querbes and Pallet do not teach discontinuation of treatment with the second therapeutic agent when the subject has the elevated level of the biomarker.
Sardh teaches that patients with recurrent AIP who were receiving scheduled hemin prophylaxis were eligible for givosiran treatment if they were willing to discontinue the treatment during the run-in and intervention periods, and further teaches monitoring urinary ALA and PBG as pharmacodynamic measures during givosiran treatment, see trail patients and Safety Assessments and Outcome Measures.
Balwani teaches selecting AHP patients based in part on elevated urinary ALA or PBG (greater than or equal to 4x ULN) and requiring discontinuation of prophylactic heme during givosiran treatment, see patients.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the methods of Querbes, as informed by Pallet, to discontinue the second therapeutic agent upon determining the elevated biomarker and administration of the ALAS1 inhibitor, as taught by Sardh and Balwani with respect to discontinuation of prophylactic hemin upon initiation of givosiran. A PHOSITA would have been motivated because discontinuing prophylactic hemin when transitioning to givosiran would avoid unnecessary concomitant treatment while permitting treatment of AHP with the ALAS1 inhibitor, thereby simplifying the treatment regimen and reducing unnecessary exposure to the second therapeutic agent. A PHOSITA would have had a reasonable expectation of success because Sardh and Balwani demonstrate that patients receiving prophylactic hemin could successfully transition to givosiran with discontinuation prophylactic hemin; thus, a PHOSITA would have reasonably expected that discontinuation the second agent upon initiation of the ALAS1 inhibitor would be successful.
Claims 54-55, 58, 60, and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Querbes W, et al., (WO2017048843A1) in view of Pallet N, et al., (Kidney Int. 2015 Aug;88(2):386-95).
Regarding claims 54, 58, 60, 64-65, Querbes teaches “diagnosis of porphyria can involve assessment of family history, assessment of porphyrin precursor levels in urine, blood, or stool, and/or assessment of enzyme activity and DNA mutation analysis,” and that “the differential diagnosis of porphyrias may involve determining the type of porphyria by measuring individual levels of porphyrins or porphyrin precursors (e.g., ALA, PBG) in the urine, feces, and/or plasma (e.g., by chromatography and fluorometry) during an attack,” which are biomarkers. Querbes further teaches that “the diagnosis of ΑIΡ can be confirmed by establishing that erythrocyte PBG deaminase activity is at 50% or less of the normal level.” See pg. 58 lines 18-26.
Regarding claim 66, Querbes teaches treating the subject is treated with a therapeutic agent that reduces the expression of ALAS1, see pg. 237 lines 9-31, pg. 240 lines 23-26, and claim 1.
Querbes does not teach wherein the biomarker is chosen from one or more renal biomarkers of KIM1, APLP1, MMP7, NGAL, CST3, or CHI3L1.
Although Querbes does not teach the claimed renal injury biomarkers, Pallet teaches NGAL, which is one of the biomarkers recited in the alternative in claim 55. Pallet teaches that “the urinary concentrations of neutrophil gelatinase-associated lipocalin” (NGAL), “a marker of tubular damage, measured in acute intermittent porphyria (AIP) patients during crisis were higher compared with those in asymptomatic carriers, indicating that acute production of ALA and PBG may promote tubular injury,” see pg. 388 column 1. Pallet further teaches “an important issue that remains to be resolved is the timing with which renal injuries occur during AIP,” see discussion.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to employ the renal injury biomarker, NGAL, in the methods of Querbes. A PHOSITA would have been motivated because employing NGAL as an additional biomarker would have provided an objective indicator of AHP-associated tubular injury that could supplement the known ALA/PBG-based diagnostic methods of Querbes, thereby facilitating earlier identification of AHP-associated renal injury. A PHOSITA would have had a reasonable expectation of success because Pallet expressly demonstrates increases urinary NGAL in AIP patients during crisis compared with asymptomatic carries, establishing that NGAL provides a detectable distinction associated with AIP disease status; thus, a PHOSITA would have reasonably expected measurement of NGAL top provide useful information for assessing whether a subject suffers from AHP.
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, 4-5, 7-10, 12, 21-24, and 26-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8-17, 37-67, and 72-78 of U.S. Patent No. 10,119,143 B2 in view of Pallet N, et al. (Kidney Int. 2015 Aug;88(2):386-95).
The ‘[143] patent claims a method of treating a porphyria, including an acute hepatic porphyria (claim 39), comprising administering to a subject a therapeutically effective amount of a dsRNA that reduces expression of ALAS1 (claim 10), the sense and antisense strands of which are sequence-identical to givosiran (claim 1), wherein the subject has an elevated level of ALA and/or PBG (claim 17) (i.e., administration of the ALAS1-reducing agent is already conditioned on a determination that the subject has an elevated level of a biomarker of AHP). The ‘[143] patent claims the subject has AHP (claim 39). Instant claims 1-2 and 7-10 recite this same method, administration of an ALAS1-reducing nucleic acid therapeutic (including givosiran) on determination of an elevated biomarker relative to a reference level, differing only in reciting the biomarker generically rather than reciting ALA/PBG specifically, and instant claims 12, 21-24, and 26-27 recite subject-selection, reference-level, and sample-type limitations already disclosed in the ‘[143] patent’s specification for the same dsRNA/method.
The primary difference between the ‘[143] patent claims and the instant claims is that instant claims 4-5 further recite that the biomarker is a renal injury biomarker (specifically KIM1, APLP1, MMP7, NGAL, CST3, or CHI3L1), whereas the ‘[143] patent does not claim these biomarkers. However, this is not a patentable distinction. Pallet teaches that urinary NGAL, a marker of tubular damage, is elevated in AIP patients during crisis compared with asymptomatic carriers, indicating that AHP-associated production of ALA and PBG promotes renal tubular injury. It would have been obvious to a person of ordinary skill in the art before the effective filing date to select NGAL as the biomarker used to determine administration of the ‘[143] patent’s ALAS1-reducing dsRNA, for the same reasons set forth 35 U.S.C. 103 rejection over Querbes in view of Pallet: NGAL provides a readily measurable, art-recognized indicator of AHP-associated renal tubular injury, and a PHOSITA would have had a reasonable expectation of success given Pallet’s express demonstration of elevated urinary NGAL in AIP patients during crisis.
Claim 25 is rejected on the ground of nonstatutory double patenting as unpatentable over claims 1, 8-17, 37-67, and 72-78 of U.S. Patent No. 10,119,143 B2 in view of Pallet (Kidney Int. 2015 Aug;88(2):386-95), as applied to claims 1-2, 4-5, 7-10, 12, 21-24, and 26-27 above, and in further view of Sardh E, et al. (N Engl J Med. 2019 Feb 7;380(6):549-558) and Balwani M, et al. (N Engl J Med. 2020 Jun 11;382(24):2289-2301).
The ‘[143] patent does not claim discontinuing a second therapeutic.
Sardh and Balwani teach discontinuing prophylactic hemin upon transitioning AHP patients to givosiran treatment, which a PHOSITA would have found obvious to incorporate into the ‘[143] patent’s claimed administration of the ALAS1-reducing dsRNA with a heme product, in order to avoid unnecessary concomitant treatment once the elevated biomarker has been addressed by the ALAS1 inhibitor.
Claims 54-55, 58, 60, and 64-66 are rejected on the ground of nonstatutory double patenting as unpatentable over claims 1, 8-17, 37-67, and 72-78 of U.S. Patent No. 10,119,143 B2 in view of Pallet (Kidney Int. 2015 Aug;88(2):386-95). The ‘[143] patent’s claim 17 and specification disclose determining that a subject has an elevated level of ALA and/or PBG relative to a reference value as a predicate to treatment with the ALAS1-reducing dsRNA, i.e., a diagnostic comparison step substantively the same as instant claim 54’s steps (a)-(c). Instant claim 66’s limitation that the subject is being treated with the ALAS1-reducing agent is likewise disclosed by ‘[143]’s claims 10-11. As with claims 4-5 above, the recitation of a renal injury biomarker (claim 55) or reduced eGFR (claim 58) in place of ALA/PBG would have been an obvious substitution in view of Pallet’s teaching that renal injury (as measured by NGAL) accompanies AHP crises, for the reasons given above.
Claims 1-2, 4-5, 7-10, 12, 21-24, and 26-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of U.S. Patent No. 11,028,392 B2 in view of Pallet N, et al. (Kidney Int. 2015 Aug;88(2):386-95).
The ‘[392] patent claims a method of treating a porphyria, including an acute hepatic porphyria (claim 18), comprising administering to a subject a therapeutically effective amount of a dsRNA that reduces expression of ALAS1 (claim 1), the sense and antisense strands of which are sequence-identical to givosiran (claim 1), wherein the subject has an elevated level of ALA and/or PBG (claim 25) (i.e., administration of the ALAS1-reducing agent is already conditioned on a determination that the subject has an elevated level of a biomarker of AHP). The ‘[392] patent claims the subject has AHP (claim 19). Instant claims 1-2 and 7-10 recite this same method, administration of an ALAS1-reducing nucleic acid therapeutic (including givosiran) on determination of an elevated biomarker relative to a reference level, differing only in reciting the biomarker generically rather than reciting ALA/PBG specifically, and instant claims 12, 21-24, and 26-27 recite subject-selection, reference-level, and sample-type limitations already disclosed in the ‘[392] patent’s specification for the same dsRNA/method.
The primary difference between the ‘[392] patent claims and the instant claims is that instant claims 4-5 further recite that the biomarker is a renal injury biomarker (specifically KIM1, APLP1, MMP7, NGAL, CST3, or CHI3L1), whereas the ‘[392] patent does not claim these biomarkers. However, this is not a patentable distinction. Pallet teaches that urinary NGAL, a marker of tubular damage, is elevated in AIP patients during crisis compared with asymptomatic carriers, indicating that AHP-associated production of ALA and PBG promotes renal tubular injury. It would have been obvious to a person of ordinary skill in the art before the effective filing date to select NGAL as the biomarker used to determine administration of the ‘[392] patent’s ALAS1-reducing dsRNA, for the same reasons set forth 35 U.S.C. 103 rejection over Querbes in view of Pallet: NGAL provides a readily measurable, art-recognized indicator of AHP-associated renal tubular injury, and a PHOSITA would have had a reasonable expectation of success given Pallet’s express demonstration of elevated urinary NGAL in AIP patients during crisis.
Claim 25 is rejected on the ground of nonstatutory double patenting as unpatentable over claims 1-37 of U.S. Patent No. 11,028,392 B2 in view of Pallet (Kidney Int. 2015 Aug;88(2):386-95), as applied to claims 1-2, 4-5, 7-10, 12, 21-24, and 26-27 above, and in further view of Sardh E, et al. (N Engl J Med. 2019 Feb 7;380(6):549-558) and Balwani M, et al. (N Engl J Med. 2020 Jun 11;382(24):2289-2301).
The ‘[392] patent does not claim discontinuing a second therapeutic.
Sardh and Balwani teach discontinuing prophylactic hemin upon transitioning AHP patients to givosiran treatment, which a PHOSITA would have found obvious to incorporate into the ‘[143] patent’s claimed administration of the ALAS1-reducing dsRNA with a heme product, in order to avoid unnecessary concomitant treatment once the elevated biomarker has been addressed by the ALAS1 inhibitor.
Claims 54-55, 58, 60, and 64-66 are rejected on the ground of nonstatutory double patenting as unpatentable over claims 1-37 of U.S. Patent No. 11,028,392 B2 in view of Pallet (Kidney Int. 2015 Aug;88(2):386-95). The ‘[392] patent’s claim 25 and specification disclose determining that a subject has an elevated level of ALA and/or PBG relative to a reference value as a predicate to treatment with the ALAS1-reducing dsRNA, i.e., a diagnostic comparison step substantively the same as instant claim 54’s steps (a)-(c). Instant claim 66’s limitation that the subject is being treated with the ALAS1-reducing agent is likewise disclosed by ‘[392]’s claims 1 and 18. As with claims 4-5 above, the recitation of a renal injury biomarker (instant claim 55) or reduced eGFR (instant claim 58) in place of ALA/PBG would have been an obvious substitution in view of Pallet’s teaching that renal injury (as measured by NGAL) accompanies AHP crises, for the reasons given above.
Claims 1-2, 4-5, 7-10, 12, 23-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 15, 24-26, 29, 31-32, 45, and 48 of copending Application No. 18630504 in view of Pallet (Kidney Int. 2015 Aug;88(2):386-95).
This is a provisional nonstatutory double patenting rejection.
‘504 claims a method of treating a porphyria by administering nucleic acid with 100% sequence identity to givosiran. The method requires the subject to have an elevated level of ALA and/or PBG, which are biomarkers of AHP. Thus, since the subject is deemed to have elevated levels of ALA and/or PBG, it is inherent that a biological sample had been obtained and an assay had been performed to determine the level of the biomarker(s). The subject as claimed can already be diagnosed or just at risk of developing a porphyria.
The primary difference between ‘504 and the instant claims is the employment of a renal biomarker selected from KIM1, APLP1, MMP7, NGAL, CST3, or CHI3L1 and the use of a second agent.
Pallet teaches that urinary NGAL, a marker of tubular damage, is elevated in AIP patients during crisis compared with asymptomatic carriers, indicating that AHP-associated production of ALA and PBG promotes renal tubular injury. It would have been obvious to a person of ordinary skill in the art before the effective filing date to select NGAL as the biomarker used to determine administration of the ‘504 ALAS1-reducing dsRNA, for the same reasons set forth 35 U.S.C. 103 rejection over Querbes in view of Pallet: NGAL provides a readily measurable, art-recognized indicator of AHP-associated renal tubular injury, and a PHOSITA would have had a reasonable expectation of success given Pallet’s express demonstration of elevated urinary NGAL in AIP patients during crisis. It would have further been obvious to use a secondary agent as ‘504 contemplated doing exactly this with heme products in combination with the RNAi, either before, concomitantly, or decreasing use of the heme product, [0145][1047][209].
Claim 25 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11, 15, 24-26, 29, 31-32, 45, and 48 of copending Application No. 18630504 in view of Pallet (Kidney Int. 2015 Aug;88(2):386-95), as applied to claims 1-2, 4-5, 7-10, 12, 23-24 above, and in further view of Sardh E, et al. (N Engl J Med. 2019 Feb 7;380(6):549-558) and Balwani M, et al. (N Engl J Med. 2020 Jun 11;382(24):2289-2301).
‘504 does not claim discontinuing a second therapeutic.
Sardh and Balwani teach discontinuing prophylactic hemin upon transitioning AHP patients to givosiran treatment, which a PHOSITA would have found obvious to incorporate into the ‘504’s claimed administration of the ALAS1-reducing dsRNA with a heme product, in order to avoid unnecessary concomitant treatment once the elevated biomarker has been addressed by the ALAS1 inhibitor.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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