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 Application, Amendments and/or Claims
1. Claims 1-20 are pending and under examination in the present application.
Information Disclosure Statement
2. The information disclosure statement (IDS) filed 01/18/2025 has been considered and the references therein are of record.
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.
3. Claims 11 and 14 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 pre-AIA the applicant regards as the invention.
Claim 11 recites “proceeding with a third [or fourth] treatment protocol if… said FFR level is within the first range”. However, the only “first range” recited in the claim is with respect to the extent of lipid-containing degenerative material in one or more blood vessels. Therefore, it is not clear whether this “first range” is the same range used for a separate cardiovascular measurement (extent of vascular lipid-containing degenerative material) or whether it represents an altogether different measurement (FFR). The metes and bounds of the claim therefore cannot be readily determined.
Claim 14 recites that the FFR level is within 1% to 79% in a second range. Claim 11, from which claim 14 depends, recites “proceeding with a second treatment protocol… if said FFR level is within a third range that is less than the FFR level within the second range.” Given this, then the “third range” would have to be <1% if it is to be lower than a “second range” that is 1% to 79% as in claim 14. Complicating the issue, claim 13 (which also depends from claim 11) also recites that the “FFR level is within 80% to 100% in a second range”; thus there are two entirely different, non-overlapping second ranges recited in the claims. The specification does not disclose the treatment of subjects having an FFR range that is below 1%, and it is not clear based upon the art that such a range can exist in a subject that is alive. Therefore, claim 14 is indefinite because it is unclear whether such a patient population having this FFR range would exist.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
4. Claims 1-2 and 4-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and natural phenomenon judicial exception without significantly more. The claim(s) recite(s) determining a treatment protocol based upon the determination of lipid-containing degenerative material present in one or more blood vessels and the degree of blood oxygen delivery in a subject. These limitations are abstract ideas, because they cover performance of the steps in the mind (i.e., observing, evaluating, forming a judgement or opinion). The natural correlation between the presence of certain pathological markers (i.e., lipid-containing degenerative material; reduced degree of blood oxygen delivery as determined by factional flow reserve (FFR)) and the presence of cardiovascular disease is also a natural phenomenon or a law of nature. Thus, the claims are directed to more than one judicial exception.
This judicial exception is not integrated into a practical application because claim 1 only recites determining a treatment protocol by monitoring or determining if a marker is present. Claim 1 describes what the treatment protocol would be if it was to be performed; however, the active performance or administration of a treatment is not actually required by the claim. Similarly, claim 11 only recites administering a diagnostic procedure involving determining the presence of certain disease markers/parameters by comparing to a predetermined range of values; the different treatment protocols are conditional upon the presence of certain determined values (i.e., proceeding with a treatment protocol if a particular diagnostic parameter is within a particular range), and “no treatment” is an option encompassed by the claims as well. Thus, the broadest reasonable interpretation (BRI) of the claims simply reads upon performing a diagnostic test because active therapy is not actually required by the claims. These determining steps must be performed in order to perform the diagnostic method, and therefore may broadly be considered as data gathering steps. As such, the claims do not integrate the abstract idea/natural correlation into a practical application because the claims do not impose any meaningful limits on practicing the method.
Finally, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps required to monitor changes in one or more blood vessels in a patient, determine the extent of lipid-containing degenerative material in one or more blood vessels, and determine FFR in a subject were routine and conventional in the art at the time of filing. For example, Tonino et al. (New Eng. J. Med. 2009, 360(3):213-224; listed on IDS) describe a method comprising monitoring the presence of lipid-containing degenerative material in blood vessels (i.e., the extent of stenosis) and determining the FFR in patients with coronary artery disease in order to determine which treatment protocol to follow. The treatment taught by Tonino was implantation of a stent, as recited in the present claims. Similarly, Mehra and Mohan (Indian Heart J. 2015, 67:77-80; listed on IDS) teach that fractional flow reserve (FFR) is an important clinical tool to assess the physiological significance of coronary lesions so as to aid in decisions on therapy. And Itu et al. (WO 2017/093337 A1; listed on IDS) indicate that in patients with stable angina, FFR is currently the “gold standard” for determining the functional severity of a lesion (see [0005]). Accordingly, the steps for monitoring changes in one or more blood vessels in a patient by determining the presence or extent of lipid-containing degenerative material in the blood vessels and monitoring a degree of blood oxygen delivery (FFR) were all procedures that were well-understood, routine and conventional in the art at the time of filing.
Note that the limitations recited in claims 2, 4, 6-9 and 12-20 describe elements of theoretical or contingent treatment protocols, or else recite predetermined ranges that better describe the values or ranges that are diagnostic of disease, and which are used to determine the type of treatment to be applied to the subject. These limitations are not active steps, nor do they limit the diagnostic methods that could be performed, and thus do not add significantly more than the recited judicial exceptions.
Accordingly, when all of the elements are considered, both individually and in combination, the claims as a whole do not amount to significantly more than the judicial exception(s). Therefore, the claims are not patent eligible.
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.
5. Claim(s) 1-2 and 4-20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tonino et al. (New Eng. J. Med. 2009, 360(3):213-224; listed on IDS).
Claim Interpretation: As discussed above, the step of “determining a treatment protocol” in the method of claim 1 does not actually require administration of the treatment. “Determining a treatment protocol” does not recite any additional active method steps, and is a mental step that could be performed entirely within the human mind, and is not obviously tied to any machine nor does it transform any article into a different state or thing. Therefore, claims dependent from claim 1 that do not explicitly require performing a treatment protocol, but rather simply define what the treatment might be (claims 6-9) or how a composition utilized by a protocol would be obtained (claims 2, 4, 20) were it to be used, do not further limit the method of claim 1.
Similarly, claim 11 recites four treatment protocols, yet in each case the treatment protocol is proceeded with the conditional if (i.e., if certain diagnostic parameters are met). Claims 12-16 aim to define the diagnostic range parameters, and claims 17-19 describe the treatment protocols. However, again, these claims do not limit the method of claim 11 because the treatment protocols are conditional; if the conditions are not met, then treatment is not performed (or that particular treatment may not be performed). The BRI of the claims thus allows for mentally defining what the treatment protocol may be even though that treatment need not be undertaken. Note also that at least one of the protocols is “no treatment”.
Tonino et al. describe a study in which patients having coronary artery disease were administered a diagnostic procedure and treated according to the results of the determined parameters. In particular, Tonino indicates that the patients were determined to have coronary lesions having stenosis of at least 50% of their diameter (see p. 214 under “Study Design”). Thus, the patients were monitored for changes in one or more blood vessels as in claims 1 and 11, and the presence of lipid-containing degenerative material in blood vessels (i.e., stenosis) was determined. Further, half of the patients were assigned to have fractional flow reserve (FFR) measured, and the results of FFR were used to determine the subsequent treatment protocol, which treatment was stent placement (see Fig. 1 at p. 215). Such teachings are therefore on point to the method of claims 1 and 11, and the limitation of claim 5 reciting measuring FFR.
Even though the treatment protocol of claim 1 is not actually performed, Tonino nonetheless anticipates the method of claims 6 and 7 in that Tonino teaches that patients having at least one stenotic lesion and having an FFR of 0.80 or less (i.e., less than 80%, which is in a range of values of 1% to 79%), these patients received stent placement (see top of p. 218). In patients having a FFR greater than 0.80, stents were not placed in the lesions (see paragraph spanning pp. 216-217). Note that such teachings also are on point to at least the first two generically recited “treatment protocols” of claim 11.
Regarding claim 10, Tonino indicates that the patients had multi-vessel coronary artery disease (see “Study Population” at p. 215). The majority of these subjects also had hypercholesterolemia (see Table 1 at p. 218).
Regarding claim 12, Tonino teaches that the subjects had an overall extent of stenosis (i.e., narrowing or occlusion caused by lesions) in the coronary artery of approximately 60% (see Table 1 at p. 219), which is within the range of 20% to 70% extent of the presence of lipid-containing degenerative material.
Regarding claims 13 and 14, Tonino indicates that an FFR of 0.80 or less identifies ischemia-causing coronary stenosis with an accuracy of more than 90% (see p. 214, left column). Therefore, subjects were divided for treatment based upon having an FFR of less than 0.80 (i.e., within 1% to 79%) or 0.80 and above (i.e., within 80% to 100%).
Placement of stents in patients having an FFR less than 0.80 is on point to the second treatment protocol of claim 18, and no stent placement in patients having an FFR greater than 0.80 addresses the fourth and third treatment protocols of claim 19, wherein both the fourth and third protocols are no treatment.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
6. Claims 1-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tonino et al. (New Eng. J. Med. 2009, 360(3):213-224) in view of Bellotti et al. (US 8,637,460 B2; published 01/28/2014) and Waksman et al. (J. Am. Coll. Cardiol. 2010, 55:2727-35) (all references listed on 01/18/2025 IDS).
The teachings of Tonino et al. are discussed above (see section 5 above) and provide for a method of treating cardiovascular disease/lipid-related disease in a patient, such as a patient having coronary artery disease, comprising performing various diagnostic procedures on the patient and determining a treatment protocol based upon the diagnostic measures, and then proceeding with a treatment. In brief, the patients’ blood vessels were monitored by angiography to determine the presence and extent of lipid-containing degenerative material in vessels (i.e., vascular plaques, lesions or stenosis). Fractional flow reserve (FFR) was also determined and used to guide treatment, wherein an FFR of 0.80 (i.e., 80%) was used as a cutoff value: patients having an FFR below 0.80 were assigned to receive stent placement. Compared to the angiography-guided strategy group (where angiographic measurements were used to plan treatment protocol instead of FFR), the number of stents used per patient and the rates of the composite end point of death, nonfatal myocaridial infarction, and repeat revascularization at one year were all significantly decreased in the FFR-guided strategy group (see abstract). Tonino further teaches that routine measurement of FFR consistently reduced the incidence of all types of adverse events by approximately 30%, and the absolute risk of major adverse cardiac events was reduced by 5 percentage points using routine FFR measurements (see paragraph spanning pp. 218-219).
Tonino therefore concludes that in patients with coronary artery disease and in need of percutaneous coronary intervention (PCI) therapy, routine measurement of FFR in addition to angiographic guidance, as compared to treatment guided by angiograph alone, results in a better overall outcome and reduction of major adverse events at one year. However, Tonino does not teach treating cardiovascular disease/lipid-related disease with a treatment protocol that comprises administering a composition derived from mixing a blood fraction of the patient with a lipid removing agent, as presently encompassed by the claims.
The teachings of Bellotti et al. and Waksman et al. are commensurate and therefore will be discussed together. Both Bellotti and Waksman disclose therapeutic methods for the treatment of vascular disease or lipid-related disease in a patient that comprises first monitoring changes in one or more blood vessels in a patient and determining if lipid-containing degenerative material is present in the one or more blood vessels. Such monitoring was performed by diagnostic coronary angiography (see p. 2730 of Waksman); both Bellotti and Waksman report the presence of vascular lesions within the patients (see, for example, Table 6 of Bellotti and Examples 8-12 of Waksman).
The therapeutic method of Bellotti and Waksman then comprises selectively delipdating high density lipoprotein (HDL) in the plasma of the patients. In particular, the delipidation technique comprises removing a unit of blood from the patient, processing the plasma by mixing it with organic solvents to create modified HDL particles with reduced lipid content, and reinfusing the plasma comprising the modified HDL particles to the patient for the treatment of cardiovascular and other lipid-associated diseases (see Bellotti, paragraph spanning cols. 12-13, and col. 13 lines 20-24). See also “Plasma collection, delipidation, and reinfusion” at pp. 2728-2729 of Waksman, which describes the method that uses plasmapheresis and reinfusion in greater detail. Such teachings are therefore on point to the recited limitations of present claims 2 and 20 with respect to the composition, and claim 3 with respect to separating blood cells from the blood to yield a blood fraction containing HDLs and LDLs (i.e., plasma).
With respect to claim 4, Bellotti indicates that the processed plasma has an increased concentration of pre-beta high density lipoproteins (preb-HDLs) compared to the pre-processed state (i.e., before being exposed to a lipid removing agent) (see col. 13 lines 6-13, and claims 7-10 at col. 34). See also Fig. 2 of Waksman showing that the average amount of pre-HDL is greatly increased in delipidated plasma compared to un-delipidated plasma.
Bellotti teaches that the modified HDL particles are administered to patients in order to reduce cellular levels of cholesterol, and can be used in the treatment of atherosclerosis, arteriosclerosis, hyperlipidemia, hypercholesterolemia, cardiovascular disease, and cerebrovascular disease (see col. 8 lines 3-18). Bellotti, for example, demonstrates the treatment of patients having coronary artery disease and peripheral vascular disease in Examples 9-12, and patients treated in the Waksman reference include those having acute coronary syndrome (ACS). Waksman teaches that, although not significant, increasing pre-HDL by acute HDL infusion therapy resulted in an almost two-fold reduction in total atheroma volume (i.e., a reduction in lipid-containing degenerative material; lesion volume) compared to statin therapy, and therefore may be useful in reducing atheroma burden with stabilization of plaques and decreasing future clinical events (p. 2734).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to have incorporated the therapeutic method of reinfusing modified HDL plasma, as taught by Bellotti and Waksman, to patients having coronary artery disease (CAD) as taught by Tonino and thereby arrive at the presently claimed invention. In particular, all of the prior art references disclose the necessity and importance of determining the state of the patient’s blood vessels (i.e., diagnostically monitoring changes in one or more blood vessels) prior to proceeding with a given intervention. Given the teachings of Tonino, the artisan would have also recognized that the information provided by determining FFR in a patient can lead to better informed medical decisions regarding stent placement in the patient, thus providing for an overall better clinical outcome. Using diagnostic information derived from different and complimentary diagnostic tests to make informed decisions about a potential therapeutic procedure is well-understood, routine and conventional in the art, and is the cornerstone of medical practice.
Similarly, it would have been obvious to have combined two or more complimentary or adjunct therapies for the treatment of the same disease, which in this case is the treatment of cardiovascular disease/lipid-associated disease with one or both of modified HDL therapy and/or stent placement. For example, in patients having a FFR higher than 0.80 (i.e., in a range of 80% to 100%), yet who have measurable atheromas in some percentage of their coronary vasculature (as encompassed by claims 8-9 and 11-19), stent placement would not be prescribed according to Tonino, but a different therapy to reduce lipid levels as taught by Bellotti and Waksman would have been recognized as an appropriate and reasonably beneficial treatment for such patients. Thus, the ability to proceed with a therapy based upon the severity of the cardiovascular condition would have be obvious in view of the prior art teachings. This is because the artisan has good reason to pursue the known options within his or her technical grasp to obtain predictable results. Such would amount to the combining of prior art elements according to known methods (i.e., diagnostic monitoring and determining an appropriate treatment based on said monitoring) to yield a predictable outcome.
Conclusion
7. No claims are allowed.
8. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. This prior art includes the following:
US 2007/0232539 A1 by Kilpatrick et al. teaches a method of introducing a delipidated high density lipoproteins (HDLs) to the bloodstream of a subject, such as for the treatment of coronary heart disease.
Sacks FM et al. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo. J. Lipid Res. 2009, 50:894-907. Describes a selective plasma delipidation procedure that converts large to small HDL, such as preb-HDL. Treatment with delipidated plasma was found to reduce diet-induced aortic atherosclerosis in monkeys.
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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