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 .
Information Disclosure Statement
The lined-through references are incomplete (no date).
Claim Objections
Claim 4 is objected to because of the following informalities: for grammatical reasons, in line 2 of the claim, the phrase “…according to…” should be deleted. (This appears to be an editing error.)
Appropriate correction is required.
Inventor’s assistance is respectfully requested in correcting any other minor grammatical and/or spelling errors which may be present in the claim set.
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 16 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.
It is unclear where the individual method steps of claim 16 are intended to be integrated with the method step sequence of claim 1 (the claim from which claim 16 immediately depends). For instance, is the chelator administration step (the first step) of dependent claim 16 performed before, or after, the first step of claim 1 (a measurement step)?
Clarification is in order.
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 1-4, 7-9 and 11-22 are rejected under 35 U.S.C. 103 as being unpatentable over Hematology (2008), 47(6), pp. 2089-2111, and, with respect to claim 15, further in view of Metallomics (2020), 12, pp. 1348-1355, both cited in the IDS.
Inventor teaches a method of treating Wilson’s disease comprising (a) measuring a serum non-ceruloplasmin bound copper level using a speciation assay and (b) controlling this level in the range of 25-130 ng/mL (independent claim 1). Dependent clam 3 (from claim 1) teaches a level of 40-80 ng/mL. Dependent claim 4 (from claim 1) teaches repeated measuring steps such that treatment is monitored. Dependent clam 14 (from claim 1) teaches that the measurement step is carried out by i) determining total serum copper level, ii) determining the serum ceruloplasmin derived copper level using a copper speciation assay, and iii) calculating the serum non-ceruloplasmin bound copper level by subtracting ii from i. Dependent claim 15 (from claim 14) teaches that i is determined using ICP-MS and ii is determined using an anion exchange chromatographic method. Dependent claim 22 (from claim 14) teaches that ii is determined using a chromatographic method. Dependent claim 16 (from claim 1) teaches administering a Cu(II) chelator and monitoring the non-ceruloplasmin bound copper level and controlling the range.
Inventor further teaches a method of monitoring treatment for Wilson’s disease comprising (a) measuring a serum non-ceruloplasmin bound copper level using a speciation assay and (b) controlling this level in the range of 25-130 ng/mL (independent claim 2). Dependent claim 17 (from claim 2) teaches the administration of a Cu(II) chelator as treatment for Wilson’s disease. Dependent clam 18 (from claim 2) teaches a level of 40-80 ng/mL. Dependent claim 19 (from claim 2) teaches repeated measuring steps such that treatment is monitored.
Inventor further teaches a method of treating Wilson’s disease comprising (a) administering a Cu(II) chelator, (b) measuring a serum non-ceruloplasmin bound copper level using a speciation assay, and (c) determining if this level is in the range of 25-130 ng/mL (independent claim 7). Dependent claim 8 (from claim 7) teaches that the chelator is trientine tetrahydrochloride or D-penicillamine. Dependent claim 20 (from claim 8) teaches that the chelator is trientine tetrahydochloride. Dependent claim 9 (from claim 7) teaches a method of treating Wilson’s disease comprising (a) administering a Cu(II) chelator, (b) measuring a serum non-ceruloplasmin bound copper level using a speciation assay, (c) determining if this level is in the range of 40-80 ng/mL, (d) modifying the chelator dose if the range is outside 40-80 ng/mL, and (e) keeping the further dose the same as the first dose if it is within the range. Dependent claim 11 (from claim 9) teaches that if the measured serum non-ceruloplasmin bound copper level after the first dose of chelator is below 40 ng/mL, then the further dose is reduced compared to the first dose, and (b) if the measured serum non-ceruloplasmin bound copper level after the first dose of chelator is above 80 ng/mL, then the further dose is increased compared to the first dose. Dependent claim 12 (from claim 11) teaches that the further chelator dose is reduced by 150-300 mg/day compared to the first dose in the case of (a), or increased by 150-300 mg/day in the case of (b). Dependent claim 21 (from claim 12) teaches that the chelator is trientine tetrahydrochloride.
Finally, inventor teaches a method of assessing a subject for susceptibility to Wilson’s disease comprising (a) measuring a serum non-ceruloplasmin bound copper level using a speciation assay, (b) determining if this level is above 150 ng/mL (independent claim 13).
Hematology (2008), 47(6), pp. 2089-2111 is a comprehensive reference which outlines a set of recommended approaches by the American Association for the Study of Liver Diseases (AASLD) for the diagnostic, therapeutic and preventative aspects of care in the diagnosis and management of Wilson’s disease (page 2089, Preamble). As the reference notes, the diagnosis of Wilson’s disease and its successful management with chelators such as trientine and D-penicillamine has been known in the art for some time (page 2090, column 1, 2nd full paragraph; page 2098, Treatment). And as the reference also notes, it has been known in the art for some time that the accumulation of copper in the liver, and subsequent injury, and the eventual release of copper into the blood stream, and deposition in other organs such as the brain, kidneys and cornea, is the result of copper not being bound to ceruloplasmin (which is a copper-carrying protein synthesized in the liver and is the major carrier for copper in the blood, accounting for 90% of the circulating copper in normal individuals) (page 2089, Introduction; page 2092, Ceruloplasmin).
Most untreated Wilson’s disease patients have a non-ceruloplasmin bound copper level above 250 µg/L (i.e. 250 ng/mL), while normal individuals have approximately 15-150 µg/L (i.e. 15-150 ng/mL) (page 2094, column 2, 1st full paragraph).
As the reference discusses, the serum non-ceruloplasmin bound copper concentration has been proposed as diagnostic test for Wilson’s disease (page 2094, column 2, 1st full paragraph). And this makes perfect sense because an elevated non-ceruloplasmin bound copper level is the crucial parameter in Wilson’s disease, and the accurate measurement, monitoring and management of this concentration within a normal range is the goal for the successful treatment of Wilson’s disease (with Cu(II) chelators, for instance). However, as the reference notes, a major problem with this approach is that this concentration is not a directly measured value, but rather one calculated from the directly measured values of (a) serum copper and (b) ceruloplasmin and subtracting (b) from (a) (page 2094, column 2, 2nd full paragraph). That being the case, as the reference notes, it is clear that inaccurate values for (a) and/or (b) will give inaccurate values for the level of non-ceruloplasmin bound copper.
A treatment of Wilsons’s disease with D-penicillamine, for instance, is outlined with comprises incremental doses of 250-500 mg/day, increased in 250 mg increments every 4-7 days, up to a maximum of 1000-1500 mg/day in 2-4 divided doses, with copper excretion in the urine monitored (page 2101, column 2, 1st and 2nd full paragraphs). Treatment protocols with trientine are similar (page 2102, column 1, Trientine).
Metallomics (2020), 12, pp. 1348-1355 teaches an LC-ICP-MS protocol for the determination of extractable copper in serum (abstract).
As Hematology (2008), 47(6), pp. 2089-2111 makes explicitly clear, it is known in the art that non-ceruloplasmin bound copper is the crucial parameter in Wilson’s disease, and that this portion of copper in the body is copper which, essentially, cannot be adequately sequestered and excreted, and whose excess, if not addressed, is uniformly fatal (as above, and page 2090, column 1, 2nd full paragraph). That being the case, it logically follows that the accurate assessment of the level of non-ceruloplasmin bound copper in Wilson’s disease patients is the crucial results-effective variable for the accurate assessment, diagnosis, treatment and overall management of Wilson’s disease. The reference notes that such a focus on the non-ceruloplasmin bound copper level has, in fact, been proposed in the art, but that there is a major problem with this approach in that the non-ceruloplasmin bound copper concentration is not a parameter which is measured directly, but rather calculated from the directly measured values of (a) serum copper and (b) ceruloplasmin. And that being the case, it logically follows that a measurement means or technique which could the improve the accuracy of the non-ceruloplasmin measurement/calculation would improve the accurate assessment, diagnosis, treatment and overall management of Wilson’s disease.
Inventor distinguishes over Hematology (2008), 47(6), pp. 2089-2111, essentially, only in that a different, more accurate, method of calculating the non-ceruloplasmin bound copper concentration is taught utilizing a “copper speciation assay.” Such an assay is defined in the instant specification as simply an assay which can separate copper bound to different species in a sample (page 29, [0090]). However, one of ordinary skill in the art, a highly skilled individual such as clinical or laboratory physician, reading the cited art, would have noted the crucial importance of the accurate measurement/calculation of the non-ceruloplasmin bound copper concentration. Furthermore, the cited prior art’s outline of the problem of this measurement/calculation intrinsically suggests its solution, and with a reasonable expectation of success: a method or technique which is able to more accurately measure/calculate the non-ceruloplasmin bound copper concentration. All other aspects of the instant invention are, essentially, simply conventional prior art protocols for the assessment, diagnosis, treatment and overall management of Wilson’s disease.
With specific respect to claim 15, one of ordinary skill in the art, a highly skilled individual such as a clinical or laboratory physician, would have found it obvious, before the effective filing date of the instant invention and absent unexpected results, to choose any conventional measurement technique(s), such as is taught by, for instance Metallomics (2020), 12, pp. 1348-1355, capable of accurately determining the total copper in a serum sample, and the proportional distribution of the copper in its bound state(s) – including non-ceruloplasmin bound copper.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN J DAVIS whose telephone number is (571)272-0638. The examiner can normally be reached M-F 8:30-5:00 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush, can be reached at 571-272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRIAN J DAVIS/Primary Examiner, Art Unit 1614 2/14/2026