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 .
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.
Current Status of 18-548,798
This Office Action is responsive to the amended claims received 27 March 2024.
Claims 1-3, 7-20, 22-30, and 32-33 are currently pending.
Priority
Applicant’s claim for the benefit of the prior-filed patent applications PCT/US2022/018672 (filed 3 March 2022), 63/165,457 (filed 24 March 2021), and 63/155,960 (filed 3 March 2021) under 35 U.S.C. 119(e), 120, 121, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) received on 28 March 2024, 9 December 2024, and 18 September 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, these information disclosure statements are being considered by the examiner.
Claim Objections
Claim 8 is objected to because of the following informalities: The phrase “less than 10% of patient’s total calories” is missing an article. This is grammatically incorrect. Applicant may choose to ament the phrase above to recite “less than 10% of the patient’s total calories”. Appropriate correction is required.
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, 7-20, 22-30, and 32-33 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.
Claim 1 recites section “d)”, which begins with the words “measuring the fasting triglyceride levels of the patient after the second dosing period”. This step, as currently written, appears to be a required step, but at the same time, the second dosing period is only applied to patients that fit the criterion of section “c)”. It is not clear if the measuring action, within section “d)” of claim 1 is always a required step within the method. This renders claims 1-3, 7-20, 22-30, and 32-33 indefinite. Applicant may choose to make it clear that the measuring action of section d) is only required wherein the criterion of section c) was met.
Claim 1 recites the phrase “a low-fat diet” four times. It is unclear to the reader whether each of these low-fat diets are: required to be the same diet, required to be different diets, or may be the same diet or different diets. This renders claims 1-3, 7-20, 22-30, and 32-33 indefinite. Applicant may choose to amend the claim to make clear which of the options above is required by the claim. For example, Applicant may choose to leave the first use of the quoted phrase above as is, and change all other uses to “the low-fat diet”, or Applicant may choose to change all uses of the phrase to “any low-fat diet”.
Claim 7 recites the phrase “a low-fat diet”, but “a low-fat diet” has already been established in the parent claim, claim 1. It is unclear to the reader if this is intended to indicate the same low-fat diet as previously established in claim 1. This renders claim 7 indefinite. Please see the proposed solutions to the similar rejection above related to claim 1.
Claim 13 recites “the patient’s liver aminotransferase (ALT/AST)”. The acronyms “ALT” and “AST” appear to indicate specific liver aminotransferases. It is not clear to the reader whether the specific liver aminotransferases in parentheses are required limitations of the claim, or are merely exemplary. This renders claims 14-18 indefinite. Applicant may choose to delete the parentheses and the acronyms therein.
Claims 15, 19-20, 22-23, and 27-30 each have a similar problem with indefiniteness. Claim 15, for example, recites “patient ALT/AST levels <3 times the ULN”. Claim 20 recites “the elevated ALT/AST test result”. It is unclear if these types of “ALT/AST” limitations indicate: either of the ALT and AST levels, both of ALT and AST levels, or the average of the ALT and AST levels. This renders claims 15-20 and 22-26 indefinite. Applicant may choose to amend the claim to specify one of the options above.
Each of claims 15-18 and 23-26 recite “the patient’s dose”. Each of these claims depend directly or indirectly upon instant claim 1, and claim 1 recites “a first daily dose”, “a second daily dose”, and “a third daily dose”. It is unclear which of these is being referred to by “the patient’s dose” within claims 15-18 and 23-26. This renders claims 15-18 and 23-26 indefinite.
Claims 15-18 each recite the reduction of “the patient’s dose”. It is unclear how the dose could be reduced when the parent claim, claim 13, states that “the patient is withdrawn from lomitapide treatment”. This renders claims 15-18 indefinite.
Claims 23-26 each recite the reduction of “the patient’s dose”. It is unclear how the dose could be reduced when the parent claim, claim 22, states that “the patient is withdrawn from lomitapide treatment”. This renders claims 23-26 indefinite.
Claim 32 recites the term “hepatic fat liver”. It is not clear to the Examiner what this term indicates. This lack of clarity is not resolved by reading the instant specification. This renders claim 32 indefinite. Applicant may choose to replace the term “hepatic fat liver” with “hepatic fat”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 27-29 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 27-29 each depend directly or indirectly upon instant claim 1. Claim 1 contains limitations, within section “b)”, that require “if the patient's fasting triglyceride levels are ≤1000 mg/dL while adhering to a low-fat diet, the patient is maintained at a daily dose of lomitapide, or a pharmaceutically acceptable salt thereof, of about 5 mg”. Each of claims 27-29 attempt to expand the scope of the limitation above. Claim 27 allows for any dose adjustments at all to meet the ≤1000 mg/dL triglyceride levels. Claim 28 allows for increasing or decreasing the lomitapide dose every 2-4 weeks, instead of maintaining the dose, as required within the quoted limitation of claim 1 above. Claim 29 allows for additional dosages that are outside of the 5 mg dose required within the quoted limitation of claim 1 above.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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 1-3, 7, 10-20, 22, 30, and 32-33 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
CEFALU (Cited by Applicant in IDS of 28 March 2024; Cefalu, A.B.; Giammanco, A.; Noto, D.; et al. “Effectiveness and safety of lomitapide in a patient with familial chylomicronemia syndrome” Endocrine (2021) 71:344–350).
The Examiner is interpreting claim 1 to be interpreted as always requiring the following: the selection of a patient having FCS, the oral administration of lomitapide (as described in section “a)”), and the measurement of the patient’s fasting triglyceride levels after the first dosing period. As currently written, claim 1 does not require the patient to adhere to a low-fat diet, but does provide additional limitations if a patient is following a low-fat diet. Therefore, all of the clauses that stem from the patient’s particular triglyceride levels in sections b-e of instant claim 1 are not interpreted to be required limitations of the claim. Instant claim 7 does require the patient to follow a low-fat diet.
CEFALU generally teaches the results of treating a single patient having familial chylomicronemia syndrome (FCS) with lomitapide (abstract). CEFALU teaches lomitapide to be an inhibitor of the microsomal triglyceride transfer protein (MTP), which was previously known to treat homozygous familial hypercholesterolemia (Pg. 345, 3rd paragraph). CEFALU teaches the administration of lomitapide for the purpose of lowering a triglyceride (TG) concentration within the patient (title and abstract).
CEFALU teaches the titration of the lomitapide dose (Pg. 346, treatment with lomitapide section). CEFALU teaches that the patient was initially provided a lomitapide dose of 5 mg/day, in addition to omega-3 fatty acids and fenofibrate (Pg. 346, treatment with lomitapide section). After 4 weeks of this dosage, the patient’s triglycerides levels were found to be 410 mg/dL, and the patient’s dosage of lomitapide was maintained at 5 mg/day for an additional 4 weeks. CEFALU satisfies the requirements of the first portion of instant claim 1 and sections “a)” and “b)”, and there is no requirement within claim 1 that sections “c)”, “d)”, or “e)” would then be performed.
CEFALU teaches that the patient was previously on a low-fat diet with a fat intake of “<20%” (case presentation section, Pg. 345), dietary restrictions were intensified before the lomitapide treatment (Pg. 346, 2nd paragraph). One of ordinary skill in the art would have understood that a fat intake of “<20 %” indicates a diet wherein less than 20 percent of the calories were provided by fat.
Regarding claim 2: Teaches that FCS can be caused by “homozygous, compound heterozygous, or double heterozygous loss-of-function mutations in genes involved in intravascular hydrolysis of TG rich lipoproteins” (introduction section).
Regarding claim 3: Teaches that FCS patients are defined by recurrent acute pancreatitis, in addition to other symptoms (abstract).
Regarding claim 7: CEFALU teaches that the patient therein was administered lomitapide, omega-3 fatty acid supplements, and fenofibrate for the treatment of FCS while adhering to a low-fat diet (Pg. 346, treatment with lomitapide section).
Regarding claims 11-12: Claims 11-12 further narrow the second and third dosing periods, but they do not require that those dosing periods be used within the method of instant claim 1. CEFALU satisfies the requirements of the first portion of instant claim 1 and sections “a)” and “b)”, and there is no requirement within claim 1 that sections “c)”, “d)”, or “e)” would then be performed. Therefore, claims 11-12 are also anticipated by CEFALU.
Regarding claims 13-18: Claim 13 states that “if the patient’s liver [enzymes] are ≥5 times the upper limit of normal… the patient is withdrawn from lomitapide treatment”. Claim 13 does not appear to require the selection of this type of patient or patient population. Therefore, claim 13 can be anticipated by any teachings that anticipate the parent claim, claim 1, unless the reference teachings are strictly related to a patient population with “liver [enzymes] are ≥5 times the upper limit of normal” and the teachings do not remove the lomitapide treatment under those conditions.
Regarding claims 19-20 and 22: Claim 19 recites “if the patient’s ALT/AST levels are from 3-5 times the ULN”. Claim 19 does not appear to require the selection of this type of patient or patient population. Therefore, claim 19 can be anticipated by any teachings that anticipate the parent claim, claim 1, unless the reference teachings are strictly related to a patient population with “ALT/AST levels are from 3-5 times the ULN” and the teachings do not require “confirming the patient’s ALT/AST levels” under those conditions.
Regarding claim 30: Claim 30 is understood to further narrow limitations of claim 1 that are not required.
Regarding claims 32-33: The outcomes within instant claims 32-33 are solely the result of administering lomitapide as described within instant claim 1. There are no positive steps recited therein that would alter these outcomes unrelated to administering the lomitapide as described within instant claim 1. Therefore, because the method of administering lomitapide as described in claim 1 has been found to be obvious, the direct outcomes of claims 32-33 are also rendered obvious.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1-3, 7-8, 10-20, 22, 30, and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over:
CEFALU (Cited by Applicant in IDS of 28 March 2024; Cefalu, A.B.; Giammanco, A.; Noto, D.; et al. “Effectiveness and safety of lomitapide in a patient with familial chylomicronemia syndrome” Endocrine (2021) 71:344–350).
Teachings of CEFALU are discussed within the rejections under 35 USC 102 above.
Regarding claim 8: CEFALU teaches that the patient was previously on a low-fat diet with a fat intake of “<20%” (case presentation section, Pg. 345), dietary restrictions were intensified before the lomitapide treatment (Pg. 346, 2nd paragraph). One of ordinary skill in the art would have understood that a fat intake of “<20 %” indicates a diet wherein less than 20 percent of the calories were provided by fat. CEFALU does not explicitly state that the patient followed a diet wherein less than 10 % of the patient’s calories came from fat.
CEFALU teaches that the low-fat diet followed by the patient was “intensified” from less than 20 % fat. It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to test a low-fat diet containing less than 10 % fat for the purpose of decreasing the triglyceride levels within a patient having FCS. The artisan would have expected success in this stricter low-fat diet, because CEFALU directly teaches a low-fat diet stricter than less than 20 % fat.
Claims 1-3, 7-20, 22, 30, and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over:
CEFALU (Cited by Applicant in IDS of 28 March 2024; Cefalu, A.B.; Giammanco, A.; Noto, D.; et al. “Effectiveness and safety of lomitapide in a patient with familial chylomicronemia syndrome” Endocrine (2021) 71:344–350)
in view of:
KOLOVOU (Kolovou, G.D.; Kolovou, V.; Papadopoulou, A.; Watts, G.F. “MTP Gene Variants and Response to Lomitapide in Patients with Homozygous Familial Hypercholesterolemia” Journal of Atherosclerosis and Thrombosis Vol. 23, No. 7, 878-883, 2016).
Teachings of CEFALU are discussed within the rejections under 35 USC 102 and 103 above. CEFALU does not provide teachings related to patients who express MTP gene variants that would improve the patient’s response to lomitapide treatment.
Regarding claim 9: KOLOVOU teaches six common variants of the MTP gene that were found to be shared by patients who were “hyper-responders” to lomitapide treatment (abstract).
It would have been obvious to one of ordinary skill in the art, before the instant effective filing date, to combine the lomitapide treatment for FCS (taught by CEFALU) with the “hyper-responder” population taught by KOLOVOU, for the purpose of providing the lomitapide treatment to the patient population who would benefit most from lomitapide. Without any teachings to the contrary, it is expected that some FCS patients would possess the MTP variants taught by KOLOVOU. The artisan would have expected success in this combination, because both references teach how to administer the same therapeutic compound, lomitapide.
Conclusion
No claims are currently allowable.
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/JDMc/Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625