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 .
Priority
The present Application, filed May 19, 2023, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/CN2021/131725, filed November 19, 2021, which claims priority to International Patent Application No. PCT/CN2020/130482, filed November 20, 2020.
Status of the Claims
In the amendment filed January 12, 2026, claims 5, 11, and 14 are canceled and new claim 20 is added. Claims 1 and 12 are amended. Claims 1-4, 6-10, 12-13, and 15-20 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 17, 2025 is acknowledged.
Previous Rejections and/or Objections
Any objections and/or rejections raised in the previous Office Action but not reiterated below are considered to have been withdrawn.
Claim Rejections - 35 USC § 112 – Modified in View of Amendment; Maintained in Substance
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 1 is indefinite:
Claim 1 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.
Claim 1 is amended to include the limitation of previous claim 11, which was previously rejected for indefiniteness. Applicant asserts that notwithstanding this, amended claim 1 is definite. Applicant contends this is so because the Office was allegedly mistaken in characterizing lupus nephritis, neuropsychiatric lupus, lupus pneumonia, lupus myocarditis, and lupus hepatitis as symptoms of lupus. Pointing to the instant specification, Applicant contends that these categories are classifications of lupus and that the recitation is therefore definite. This argument has been fully considered, but is not found persuasive.
The original claim language of claim 11, prior to the amendment of January 8, 2025, was that the systemic lupus erythematosus “includes” lupus nephritis, neuropsychiatric lupus, etc. This was reasonably clear as indicating that the method for treating systemic lupus erythematosus that further included one or more of the listed complications/manifestations (the word “symptom” itself is immaterial). With the amendment of January 8, 2025, this was changed to recite that systemic lupus erythematosus “is selected from” lupus nephritis, neuropsychiatric lupus, etc. This created a category error, as the various listed entities are properly understood as symptoms/complications/manifestations of systemic lupus erythematosus rather than distinct sub-types. See, for example, the non-patent publication, Lupus Nephritis, a Cleveland Clinic webpage found at the url my.clevelandclinic.org/health/diseases/21809-lupus-nephritis, last updated in 2021, which states, “Lupus nephritis is inflammation and damage in your kidneys due to systemic lupus erythematosus (SLE).” As such, lupus nephritis is properly understood as a physical manifestation that results from SLE, not as something that SLE “is” (as the phrase “is selected from” suggests). As an comparison, Alzheimer’s disease and Parkinson’s disease are distinct types of neurodegenerative disease, and a neurodegenerative disease can be selected from Alzheimer’s or Parkinson’s. Conversely, memory loss and alterations in mood are manifestations or symptoms of Alzheimer’s and Alzheimer’s can be characterized by those things, but it cannot properly be said to “be” (or be “selected from”) those things.
Beyond a mere category error, though, the “is selected language” creates genuine ambiguity about the meaning of the recitation. When the SLE “includes” the various manifestations, it is clear that this refers to a scenario where the SLE is characterized by any or all of them. However, when the SLE “is selected from” the various manifestations, this suggests mutually exclusive alternative species of SLE, and renders it unclear whether an SLE characterized by multiple of the recited manifestations is included or excluded. The rejection, modified to apply to amended claim 1, is maintained.
Reiterated, albeit modified, rejection:
Claim 1 is indefinite for reciting “wherein systemic lupus erythematosus is selected from the group consisting of lupus nephritis, neuropsychiatric lupus, lupus pneumonia, lupus myocarditis and lupus hepatitis,” because one of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. The listed conditions beginning with lupus nephritis are symptoms of systemic lupus, and it represents a category error to recite that the disease “is selected from” its possible symptoms. As noted above, it also creates ambiguity whether the recitation includes cases of SLE in which multiple of the recited complications are present, or whether it is exclusive to cases in which one and only one of the recited complications is present. Claim 1 will be construed, according to a broadest reasonable interpretation as reciting that the systemic lupus erythematosus is characterized by at least one symptom or manifestation selected from the group consisting of lupus nephritis, etc.
Claim Rejections-- 35 USC § 103 – Modified in View of Amendment – Maintained in Substance
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.
Claims 1-4, 6-10, 13, and 15-19 are obvious over He and Lorenzo-Vizcaya:
Claims 1-4, 6-10, 13, and 15-19 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent No. 10,098,900 to He (hereinafter, “He”), in view of the non-patent publication, Bruton’s Tyrosine Kinase Inhibitors: A New Therapeutic Target for the Treatment of SLE?, Immunotargets and Therapy, 9, pgs. 105-110 (2020) by Lorenzo-Vizcaya et al. (hereinafter, “Lorenzo-Vizcaya”).
Amended claim 1 is identical in scope to previous claim 11, which was rejected for obviousness over He and Lorenzo-Vizcaya a. Applicant makes no argument specific to the previous prima facie case of obviousness of claim 11. Applicant does however discuss the case of obviousness of claim 2, in a manner that is perhaps applicable to all claims. Applicant first discusses inherency, ending with a conclusory assertion that, while treatment of an underlying SLE may treat a consequent lupus nephritis, it would not necessarily treat the consequent lupus nephritis (pg. 8 of Applicant’s Response, fourth paragraph).
This argument has been fully considered, but is not found persuasive. As a first matter, while the rejection notes it is arguable that the method of treating SLE is intrinsically a method for treating lupus nephritis, the rejection does not rely on this. To the argument that treating SLE intrinsically treats a resultant lupus nephritis, note the non-patent publication, Lupus Nephritis, Merck Manual Prof. Version website, by O’Brien and obtained at the url www.merckmanuals.com/professional/nephrology/glomerular-disorders/lupus-nephritis, which states that “Treatment [of lupus nephritis] is of the underlying disorder” (opening summary paragraph). Stated alternatively, in order to treat lupus nephritis, one must necessarily treat the underlying SLE; or conversely, treatment of an underlying SLE necessarily also constitutes treatment of any consequent lupus nephritis. Thus, Applicant’s conclusory assertion that a method for treating lupus nephritis does not necessarily “flow from” the teaching of a method of treating SLE is not found persuasive. Regardless, as noted, the rejection did not ultimately depend on an insertion that SLE treatment intrinsically constitutes lupus nephritis treatment, but instead relied on the teaching of Lorenzo-Vizcaya.
To that point, Applicant argues that Lorenzo-Vizcaya discloses tests of BTK inhibitors that are “significantly structurally different from” claimed Compound 1, and it is well-known in medicinal chemistry that minor structural differences can result in substantial differences in activity. On this basis, Applicant contends that one of skill in the art could not reasonably predict that Compound 1 can be useful for treating lupus nephritis. This argument has been fully considered but is not found persuasive.
First, the assertion of “significant structural differences” is subjective, and there are certainly some obvious structural similarities between instant Compound 1 and the specific examples of Lorenzo-Vizcaya. Furthermore, the different examples of Lorenzo-Vizcaya are as structurally distinct from one another as they are from instant Compound 1. But regardless of this, and also highlighted by the fact the Lorenzo-Vizcaya cites multiple different examples, the teaching of Lorenzo-Vizcaya is not tied to any particular structure, but to the role of BTK inhibition as plausible treatment for SLE and consequently for lupus nephritis. To that point, Lorenzo-Vizcaya makes a general observation, not tied to a specific structure or inhibitor, regarding “the therapeutic potential for BTK inhibition in lupus nephritis.” In view of this teaching, one would have had a reasonable expectation of success in using a BTK inhibitor to treat lupus nephritis.
Applicant further points to the non-patent publication, Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial, Arthritis Rheumatol., 73, pgs. 1835-1846 (2021) by Isenberg et al. as evidence that not all BTK inhibitors are necessarily useful for treating lupus. It is unclear what this is meant to rebut, as the rejections do not rely on a premise that all BTK inhibitors are necessarily clinically useful for the treatment of SLE. It relies primarily on the teaching from He that of a method of treating SLE comprising administering a BTK inhibitor to the patient, and secondarily on the teaching of Lorenzo-Vizcaya (which notes the fenebrutinib clinical study of Isenberg) that BTK inhibitors that are effective against SLE are likely also to be effective against its consequent manifestations like nephritis. As such, the example of fenebrutinib’s clinical failure to treat SLE is not relevant to the reasons for rejection.
For the aforementioned reasons, the rejections, as modified in view of the amendments, are maintained.
Modified but substantially reiterated rejection:
Claim 1 recites a method for treating systemic lupus erythematosus, the method comprising administering to a subject in need thereof a therapeutically effective amount of (S)-7-(1-acryloylpiperidin-4-yl)-2-( 4-phenoxyphenyl)-4,5,6, 7-tetrahydropyrazolo-[ 1,5-a ]pyrimidine-3-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof,
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As amended, claim 1 further recites wherein systemic lupus erythematosus is selected from (is characterized by a disorder selected from) lupus nephritis, neuropsychiatric lupus, lupus pneumonia, lupus myocarditis, and lupus hepatitis.
He teaches a method for treating an immune disorder, such as an autoimmune disease, comprising administering to a subject in need a therapeutically effective amount of (a) a Bruton tyrosine kinase (BTK) inhibitor, and (b) a mammalian target of rapamycin (mTOR) kinase inhibitor (col. 2, lines 54-60). He teaches an exemplary autoimmune disease to be treated is systemic lupus erythematosus (col. 2, lines 56-57) and an exemplary BTK inhibitor to be used is BGB-3111. BGB-3111 is Compound 1 of instant claim 1, as evidenced by the non-patent publication, Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase, J. Med. Chem., 62, pgs. 7923-7940 (2019) by Guo et al. (hereinafter, “Guo”). See, for example, the Guo Abstract, showing a line drawing of BGB-3111. It will be understood that Guo is not cited as a secondary prior art reference in this rejection, but is only cited to establish that the BGB-3111 of He is Compound 1 of instant claim 1. He thus teaches a method of treating systemic lupus erythematosus, comprising administering to a subject in need thereof a therapeutically effective amount of instant Compound 1.
While He does not explicitly mention that the systemic lupus erythematosus (SLE) to be treated may be characterized by one of the cited complications (lupus nephritis, et al.), it is arguable that the method of treating SLE of He intrinsically treats whichever of the various common manifestations or complications of SLE may be present, such as lupus nephritis. See, for example, the non-patent publication, Lupus Nephritis, Medscape website, obtained at the url emedicine.medscape.com/article/330369-overview (last updated in 2023) by Brent (hereinafter, “Brent”). Brent states that “Lupus nephritis is clinically evident in 50-60% of patients with systemic lupus erythematosus (SLE), and it is histologically evident in most SLE patients, even those without clinical manifestations of kidney disease.” As such, the method for treating SLE could reasonably be regarded as also intrinsically being a method of treating lupus nephritis.
Notwithstanding this, it would have been obvious to apply the method of He to the treatment of SLE including cases which manifest lupus nephritis, because it was known in the art that administration of a BTK inhibitor could treat lupus nephritis as an adjunct to treating SLE. See, for example, Lorenzo-Vizcaya.
Lorenzo-Vizcaya reviews what was known and published (as of 2020) regarding the treatment of human SLE and animal models of SLE using BTK inhibitors (Abstract). Lorenzo-Vizcaya teaches that, in at least three different animal models of lupus, different BTK inhibitors were effective to limit or prevent lupus nephritis (pg. 107, Nephritis, first five paragraphs). Summarizing, Lorenzo-Vizcaya indicates that these results emphasize the therapeutic potential for BTK inhibition in lupus nephritis (pg. 107, Nephritis, last sentence). It thus would have been obvious to apply the method of He to the treatment of cases of SLE which manifest the common complication, lupus nephritis, as evidenced by Lorenzo-Vizcaya.
Similarly, with respect to claim 2, it would have been obvious to apply the method of He for the express purpose of treating lupus nephritis, in view of the leaching of Lorenzo-Vizcaya that BTK inhibitors, like the Compound 1 of He, are effective to treat murine models of lupus nephritis.
With respect to claim 3, Lorenzo-Vizcaya teaches that administration of a BTK inhibitor in lupus model mice inhibited glomerular antibi and C3 deposition as well as caused a significant dose-dependent reduction of inflammatory infiltrates and glomerular lesions (pg. 107, Nephritis, first paragraph). On the basis of these findings, one would have had a reasonable expectation of success in applying the method of He to the treatment of active proliferative lupus nephritis.
Claims 4 and 13 recite the method of claim 1 and 2, respectively, wherein the subject is a patient who meets an inclusion criterion selected from three listed, such as positive antinuclear antibodies, positive anti-dsDNA autoantibody, and/or positive anti-Smith autoantibody at screening. He is applied to claims 4 and 13 as to claim 1, but does not explicitly teach this feature. It would have been obvious to apply the method of He to an SLE patient meeting at least one of these inclusion criteria, however, because the potential utility of BTK inhibition for the treatment of such patients was known in the art, as demonstrated, for example by Lorenzo-Vizcaya. In particular, Lorenzo-Vizcaya teaches that SLE is an autoimmune disease characterized by autoantibodies against nuclear antigens and that that BTK+ cells in the peripheral blood of SLE patients correlates with anti-dsDNA antibodies, among other things (pg. 106, left column, first full paragraph). Lorenzo-Vizcaya further teaches that B cell depletion is associated with a fall in antibodies to DNA (pg. 106, paragraph spanning bottom of left column to top of right column), and the BTK is an essential intracellular signaling molecule in the development, survival, and activation of B cells (pg. 105, Introduction, first paragraph). Given these points, it would have been obvious to apply the method of He to a SLE patient who, like many SLE patients, is positive for anti-dsDNA autoantibody, because the BTL inhibitor of He would be expected, per Lorenzo-Vizcaya, to result in B cell depletion which would in turn be expected to result in a decrease an anti-dsDNA autoantibody.
With respect to claims 6-7 and 9, He teaches that the daily dose of the BTK inhibitor can be between 5 mg and 1000 mg (col. 6, lines 19-20). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, (CCPA 1976). See also MPEP 2144.05(I).
With respect to claim 8, He further teaches that the BTK inhibitor can be orally administered to the subject one or more times daily (col. 6, lines 16-18). This, in conjunction with the daily dose cited above, encompasses the twice daily oral administration of claim 8. As such, the recited dose of claim 8 likewise lies inside the range disclosed by the prior art, and is prima facie obvious.
With respect to claims 10 and 19, similar to claims 4 and 13, it would have been obvious in view of the teaching of Lorenzo-Vizcaya that BTK+ cells in the peripheral blood of SLE patients correlates with anti-dsDNA antibodies, to apply the method of He to a subject who is positive for anti-dsDNA IgG in serum. With respect to claim 12, as noted above, this claim does not further limit claim 2. Claim 12 is thus obvious for the same reasons as is claim 2. In particular, when applying the method of He and Lorenzo-Vizcaya for the treatment of lupus nephritis, one would necessarily be treating a subject who has one of the six classes of lupus nephritis recited in claim 12.
With respect to claims 15-16 and 18, He teaches that the daily dose of the BTK inhibitor can be between 5 mg and 1000 mg. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, (CCPA 1976). See also MPEP 2144.05(I).
With respect to claim 17, He further teaches that the BTK inhibitor can be orally administered to the subject one or more times daily (col. 6, lines 16-18). This, in conjunction with the daily dose cited above, encompasses the twice daily oral administration of claim 17. As such, the recited dose of claim 17 likewise lies inside the range disclosed by the prior art, and is prima facie obvious.
Claims 12 and 20 are obvious over He, Lorenzo-Vizcaya, and Markowitz:
Claims 12 and 20 are rejected under 35 U.S.C. § 103 as being unpatentable over He, in view of Lorenzo-Vizcaya, and further in view of the non-patent publication, Classification of lupus nephritis, Curr. Opin. Nephr. Hyperten., 18, pgs. 220-225 (2009) by Markowitz et al. (hereinafter, “Markowitz”).
Claim 12 recites the method of claim 2 wherein lupus nephritis is minimal mesangial lupus nephritis, mesangial proliferative lupus nephritis, or focal lupus nephritis. Claim 20 recites the method of claim 2 wherein lupus nephritis is diffuse segmental (IV-S) or global (IV-G) lupus nephritis, membranous lupus nephritis, or advanced sclerosing lupus nephritis.
He and Lorenzo-Vizcaya are applied to claims 12 and 20 as to claim 2, above, but neither expressly recites wherein the lupus nephritis is one of the recited types. It would have been obvious, however, to apply the method of He and Lorenzo-Vizcaya to cases of lupus nephritis belonging to one of the types of claim 12 or to one of the types of claim 20 because, cumulatively, these represent all types of lupus nephritis. See, for example, Markowitz.
Markowitz reviews the classifications of lupus nephritis according to the International Society of Nephrology (Purpose of review). Markowitz teaches that all types of lupus nephritis are encompassed by claims 12 and 20, half being encompassed by claim 12 and half being encompassed by claim 20 (compare Markowitz Table 1, reproduced below, to the listed types of lupus nephritis in claims 12 and 20).
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Given that claim 12 limits the lupus nephritis to be treated to half of the possible types, and claim 12 limits it to the other half of possible types, and given that Lorenzo-Vizcaya teaches the likelihood of success generally in treating lupus nephritis with BTK inhibitors, it would have been obvious to try application of the method of He and Lorenzo-Vizcaya to either the sub-group of nephritis types of claim 12 or of claim 20, and one would have had a reasonable expectation of success in doing so. Claims 12 and 20 are therefore obvious.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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