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 .
Election/Restrictions
Applicant’s election without traverse of Group II, corresponding to claims 26-30 and 35-40, in the reply filed on October 31, 2025, is acknowledged. Further, Applicant elected a fibrate. Claims 26-28 and 38-40 of Group II read on the elected species.
Status of the Claims
Claims 1, 14, 26-30, 35-40 are pending. Claims 1, 14, 29, 30, and 35-37 are withdrawn. Claims 26-28 and 38-40 are examined.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
Claims 38-40 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 38 requires “further” determines a level and administering a fibrate ,e.g., when levels are low. However, claim 26 already requires administering a fibrate, e.g. It appears that claim 38 is now attempting to make the required administration step of claim 26 optional and dependent upon confirming a reduction in expression. This is confusing, not further limiting, and removes any administration step if a measured level is, e.g., not exhibiting of a reduced level. If, e.g., a sample does not show a reduction, then claim 38 would appear to require no administration at all. In this respect, claim 38 is not further limiting unless all subjects with dry AMD have low levels of PGC-1α. Clarification is requested.
If a subject is already diagnosed with dry AMD, the prior art teaches treating them with a fibrate. If they are not diagnosed, it is not clear how a skin biopsy for a level of PGC-1α positively identifies that subject as having dry AMD to the exclusion of other conditions in which levels of PGC-1α are lower than a control. As drafted, the “determining” steps of claims 38-40 do not appear to alter treatment, which is administering fenofibrate, e.g., to a subject with dry AMD. The determining step appears to identify/assess a known natural correlation of a biomarker in a subject. Clarification is requested.
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.
Claims 38-40 are rejected under 35 U.S.C. 101 because the claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, and they do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
The claimed invention is directed to a judicial exception (i.e., law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claims 38-40 are directed towards a law of nature. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The examiner has determined that the claimed processes have not transformed unpatentable natural laws into patent eligible applications of those laws. As such, he concludes that the processes instantly claimed are not patent eligible based upon the analysis set forth below. Also see M.P.E.P. § 2106.01 and 2014 Interim Guidance links at: http://www.uspto.gov/patents/law/exam/interim_guidance_subject_matter_eligibility.jsp.
STEP 1: Are the claims to a process, machine, manufacture, or composition of matter? YES.
Claims 38-40 are drawn to a process or protocol (series of steps to be taken), to determine or assess a level of a biomarker in a subject.
STEP 2A: Are the claims directed to a law of nature, natural phenomenon, or an abstract idea? YES.
The claims are “directed to” a law of nature, natural phenomenon, an abstract idea (i.e., the exception is recited in the claims). More specifically, the claims are directed to evaluating a correlation in a subject’s body when they have a condition without a required administration step for treatment.
Claims 38-40 purport to apply natural laws or natural phenomenon describing providing a skin sample and determining an activity level in that sample. The examiner must determine, below, whether the claimed processes have transformed these unpatentable natural laws into patent eligible applications of those laws. As analyzed in Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. -__ (2012), 132 S. Ct. 1289.
The instant claims effectively claim natural laws or natural phenomenon- namely the recognition of a trend or activity level in a subject population. There is no required step of administering because the phrase “when there is a reduction” is recited in dependent claim 38. This is interpreted to mean that when there is not a reduction, no step is taken. Further, if there is always a reduction, this sample if merely confirming a natural correlation in an already identified subject population. Claims 38 and 39 only require determining a correlation.
The administration step limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). In the instant case, a sample is taken, but the use of knowledge that a level is decreased and confirming that decrease does not alter the active step, but rather it confirms an already known correlation. That correlation is the reduction of PGC-1α in subjects with dry AMD.
STEP 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception? NO.
In particular, the claimed step under a broadest reasonable interpretation includes determining a level and then doing nothing. When the calculation is made even obtained from a skin sample, nothing else is required unless a reduction compared to normal levels is shown. Further, it is not dispositive whether or not such calculation can be made with or without a machine or device. Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer. As the Federal Circuit has explained, "[c]ourts have examined claims that required the use of a computer and still found that the underlying, patent-ineligible invention could be performed via pen and paper or in a person’s mind." Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1335, 115 USPQ2d 1681, 1702 (Fed. Cir. 2015).
Optional And Conditional Steps May Have No Patentable Weight: In re Johnston (Fed. Cir. 01/30/06) (“optional elements [“may be”] do not narrow the claim because they can always be omitted”); In re Schulhauser (PTAB 04/28/16) (precedential).
In INO Therapeutics LLC v. Praxair Distribution Inc., 782 Fed.Appx. 1001, 1005 (Fed. Cir. 2019) (not precedential), the Federal Circuit held that claims directed to a “method of treating patients who are candidate for inhaled nitric oxide treatment” were “directed to [a] natural phenomenon” and not patent eligible. The Court noted that, unlike the claims at issue in Vanda, when analyzed as a whole, the claim is not directed to “a new way of actually treating the underlying condition of hypoxic respiratory failure,” but instead the focus is directed to “screening for a particular adverse condition that, once identified, requires iNO treatment be withheld.” Id. at 1007.
In the instant case, the claims encompass assessing a level or determining a level.
Here, the examiner believes that the instant claims do not add enough to their statements of assessing a correlation to allow the processes they describe to qualify as patent-eligible processes that apply natural laws. In other words, the instant claims do not recite additional elements that amount to significantly more than the judicial exception. More particularly, it is not clear that such measurement or determination yields a method that differs in any way from administering a fibrate to a subject with dry AMD. If, e.g., the level measured is low and we therefore administer a fibrate, this does not add anything to prior art that already teaches treating dry AMD by administering a fibrate and the knowledge that levels of biomarker are low in those subjects.
First, the instantly claimed “determining step” means measuring a known non-specific biomarker. The marker is non-specific because without more, a conclusion that a subject has dry AMD cannot be made.
Second, the phrase “when there is a reduction” means that any additional step may not be undertaken at all.
In conclusion, the determining step required by the claims may have limited application. The determining step uses a high level of general language that covers merely screening a subject- whether or not they qualify as a subject to be treated under the present claims. For the reasons stated above, the examiner concludes that the instant claims are effectively methods of performing a mental screening.
In accordance with compact prosecution, all claims are fully examined below under each of the other patentability requirements.
Claim rejections – 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 26-28 are rejected under 35 U.S.C. 103(a) as being unpatentable over Wassel et al. in US 2014/0275263 et al.(cited in IDS), in view of Chiras et al. in Critical Reviews in Clinical Laboratory Sciences, 52(1): 12 – 27 (2015) (cited in IDS), and in view of del V Cano et al. in PPAR Research Volume 2008, Article ID 821592, 5 pages (2008) (cited in IDS).
Wassel teaches formulations for topical delivery of therapeutically effective amounts of lipophilic APIs to treat eye conditions, including age-related macular degeneration, including dry age-related macular degeneration. See par.’s 127-129. The API in the composition can be fenofibrate. See Abstract. A concentration can be 0.5% or 3% fenofibrate, as examples. See par.’s 43 and 44.
Further, Chiras teaches epidemiologic, genetic and molecular studies support a major role for oxidative stress in the development of dry AMD and that understanding the early molecular events in the pathogenesis and the exact role of oxidative stress in dry AMD may provide novel opportunities for therapeutic intervention for the prevention of progression to advanced disease (See Abstract, p15). Chiras teaches that oxidative stress refers to cellular or molecular damage caused by reactive oxygen species, which especially occurs in age-related conditions as a result of an imbalance between the production of reactive oxygen species and the antioxidant defense response. Chiras teaches the antioxidants used to minimize oxidative stress include the major antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase and none-enzyme molecules such as glutathione (GSH) (page 13, Figure 1). Overall, Chiras sets forth a mechanistic basis for treating dry AMD; i.e. minimizing role of oxidative stress, caused by reactive oxygen species.
Moreover, Del V Cano teaches PPAR-α as potential therapeutic agents for the treatment of AMD. Del V Cano teaches biological pathways important to the onset and progression of dry AMD include immune modulation, lipid regulation and oxidant/antioxidant pathways. See Abstract.
Del V Cano teaches fenofibrate is a ligand known to activate PPAR-α (which is present in the retina) and that activation of PPAR-α may have a potential role in oxidant/antioxidant pathways now strongly implicated in the pathogenesis of dry AMD. See page 2.
Del V Cano teaches there is a substantial literature linking oxidative damage to dry AMD pathogenesis and that PPAR-α could theoretically inhibit AMD progression via effects on oxidative pathways. Del V Cano teaches it has been previously reported that PPAR-α activation induces the expression and activation of antioxidant enzymes, such as super oxide dismutase and glutathione peroxidase. Del V Cano teaches antioxidants can provide direct protection to the retina as supported by a clinical trial adding antioxidants to the routine care of dry AMD. Del V Cano teaches because fenofibrates PPAR-α activators (or agonists) have an established safety profile, when administered orally and it is important to examine the potential beneficial effects of fenofibrate on onset and progression of nonneovascular “(dry)” AMD disease and conversion from dry to wet AMD disease. See page 3.
The combination of Wassel, Chiras and del V Cano renders prima facie obvious a method of treating dry AMD by administering a fibrate, such as the PPARα agonist compound fenofibrate to a subject in need thereof with a reasonable expectation of success because oxidative stress plays a major role in the development of dry AMD and because fenofibrate is an antioxidant, known to activate antioxidant enzymes, such as super oxide dismutase and glutathione peroxidase, and thus will reduce oxidative stress.
It would have been prima facie obvious to one of ordinary skill in the art prior to the filing date of the claimed invention to administer a claimed fibrate to a subject with dry AMD. This is taught by Wassel. Further, Chiras sets forth a mechanistic basis for treating dry AMD; i.e. minimizing role of oxidative stress, caused by reactive oxygen species while del V Cano teaches a fibrate to work through such mechanistic bases and notes that fenofibrate through those specific mechanisms can treated dry AMD. As such, there is a reasonable and predictable basis that a claimed agent will treat a subject with AMD and that such administration will have a claimed effect secondary to administration as a known mechanistic basis for mitigating dry AMD.
Claims 26-28 and 38-40 are rejected under 35 U.S.C. 103(a) as being unpatentable over Wassel et al. in US 2014/0275263 et al., in view of Chiras et al. in Critical Reviews in Clinical Laboratory Sciences, 52(1): 12 – 27 (2015), del V Cano et al. in PPAR Research Volume 2008, Article ID 821592, 5 pages (2008) and Egger et al. in PLosOne 7(2), 1 – 12 (2012) (cited in IDS), in view of Roggia et al., αvβ5 Integrin/FAK/PGC-1α Pathway Confers Protective Effects on Retinal Pigment Epithelium,” PLOS One, published August 5, 2015 (cited in IDS), and in view of Zhang et al., “Derivation, culture and retinal pigment epithelial differentiation of human embryonic stem cells using human fibroblast feeder cells,” J Assist Reprod Genet (2012) 29:735-744.
Wassel teaches formulations for topical delivery of therapeutically effective amounts of lipophilic APIs to treat eye conditions, including age-related macular degeneration, including dry age-related macular degeneration. See par.’s 127-129. The API in the composition can be fenofibrate. See Abstract. A concentration can be 0.5% or 3% fenofibrate, as examples. See par.’s 43 and 44.
Wassel does not teach the steps of determining expression or activity levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α).
Chiras teaches epidemiologic, genetic and molecular studies support a major role for oxidative stress in the development of dry AMD and that understanding the early molecular events in the pathogenesis and the exact role of oxidative stress in dry AMD may provide novel opportunities for therapeutic intervention for the prevention of progression to advanced disease (See Abstract, p15). Chiras teaches that oxidative stress refers to cellular or molecular damage caused by reactive oxygen species, which especially occurs in age-related conditions as a result of an imbalance between the production of reactive oxygen species and the antioxidant defense response. Chiras teaches the antioxidants used to minimize oxidative stress include the major antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase and none-enzyme molecules such as glutathione (GSH) (page 13, Figure 1). Overall, Chiras sets forth a mechanistic basis for treating dry AMD; i.e. minimizing role of oxidative stress, caused by reactive oxygen species.
Del V Cano teaches PPAR-α as potential therapeutic agents for the treatment of AMD. Del V Cano teaches biological pathways important to the onset and progression of dry AMD include immune modulation, lipid regulation and oxidant/antioxidant pathways. See Abstract.
Del V Cano teaches fenofibrate is a ligand known to activate PPAR-α (which is present in the retina) and that activation of PPAR-α may have a potential role in oxidant/antioxidant pathways now strongly implicated in the pathogenesis of dry AMD. See page 2.
Del V Cano teaches there is a substantial literature linking oxidative damage to dry AMD pathogenesis and that PPAR-α could theoretically inhibit AMD progression via effects on oxidative pathways. Del V Cano teaches it has been previously reported that PPAR-α activation induces the expression and activation of antioxidant enzymes, such as super oxide dismutase and glutathione peroxidase. Del V Cano teaches antioxidants can provide direct protection to the retina as supported by a clinical trial adding antioxidants to the routine care of dry AMD. Del V Cano teaches because fenofibrates PPAR-α activators (or agonists) have an established safety profile, when administered orally and it is important to examine the potential beneficial effects of fenofibrate on onset and progression of nonneovascular “(dry)” AMD disease and conversion from dry to wet AMD disease. See page 3.
The combination of Wassel, Chiras and del V Cano renders prima facie obvious a method of treating dry AMD by administering a fibrate, such as the PPARα agonist compound fenofibrate to a subject in need thereof with a reasonable expectation of success because oxidative stress plays a major role in the development of dry AMD and because fenofibrate is an antioxidant, known to activate antioxidant enzymes, such as super oxide dismutase and glutathione peroxidase, and thus will reduce oxidative stress.
Wassel, Chiras and del V Cano do not teach or suggest the steps of determining expression or activity levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in a sample obtained from the subject as recited in instant Claim 38.
Egger teaches peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) proteins are key regulators of cellular bioenergetics and are accordingly expressed in tissues with a high energetic demand. See Abstract. More specifically, Egger teaches PGC-1α is found at high levels in the retina and most prominently in the photoreceptors, 2) PGC-1α knockout mice suffer from a striking deterioration in retinal morphology and function upon detrimental light exposure, 3) Gene expression studies revealed dysregulation of all major pathways involved in retinal damage and apoptosis, repair and renewal in the PGC-1α knockouts, and 4) PGC-1α is a central coordinator of energy production and, importantly, all of the major processes involved in retinal damage and subsequent repair. See Abstract. Egger teaches that PGC-1α might be an attractive target for therapeutic approaches aimed at retinal degeneration diseases. See Abstract. Eggers teaches reduced levels of PGC-1α in retinal disease models. See Figures 1C and 1D.
Egger teaches pathological conditions of the retina such as age-related macular degeneration is associated with excess generation of reactive oxygen species (ROS), inflammation and endoplasmic reticulum stress, which result in apoptosis and tissue degeneration; wherein PGC-1α affects these processes by promoting ROS detoxification, ameliorating endoplasmic reticulum stress and modulating tissue as well as systemic inflammation. See p2.
Eggers also teaches PGC-1α promotes reactive oxygen species (ROS) detoxification in the retina, wherein an excess of ROS, is associated with age-related macular degeneration.
Roggia teaches AMD is associated with age-related abnormalities in the retinal pigment epithelium, among other tissues. Roggia explains the following at page 13:
Dry and wet AMD are the late stages of AMD, wherein the degeneration cannot be fully reversed. Choriocapillaris is maintained by VEGF secretion from RPE cells; the results of our previous study reveal that PGC-1α is an important regulator of VEGF expression in RPE cells, particularly in response to POS phagocytosis. Therefore, a therapeutic approach targeting PGC-1α at the early stage of AMD may suppress the progression of this disease.
Aging phenotypes in RPE are identified in PGC-1α deficient mice. Several compounds proposed to treat early stage AMD include those that induce PGC-1α. See p13. Roggia concludes: “In conclusion, we have found that the αvβ5 integrin/FAK/PGC-1α pathway is involved in POS-induced PGC-1α upregulation, which confers protective effects on RPE cells.” P14, 1st par. Further, the following is described with respect to dry AMD in the first full paragraph on page 13.
We identified accelerated aging phenotypes in RPE, Bruch’s membrane, and choriocapillaris of PGC-1α-deficient mice. The loss of choriocapillaris with age and in the early stage of AMD has been confirmed in humans. Moreover, loss of choriocapillaris and thickening of the Bruch’s membrane hampers nutrient supply to RPE cells and metabolite release from those cells, leading to RPE loss (i.e., dry AMD).
Thus, it appears that the nexus between dry AMD and PGC-1α is clear.
It would have been prima facie obvious to one of ordinary skill in the art prior to the filing date of the claimed invention to administer a claimed fibrate to a subject with dry AMD. This is taught by Wassel. Further, Chiras sets forth a mechanistic basis for treating dry AMD; i.e. minimizing role of oxidative stress, caused by reactive oxygen species while del V Cano teaches a fibrate to work through such mechanistic bases and notes that fenofibrate through those specific mechanisms can treated dry AMD. As such, there is a reasonable and predictable basis that a claimed agent will treat a subject with AMD and that such administration will have a claimed effect secondary to administration as a known mechanistic basis for mitigating dry AMD. Further, Egger teaches i) pathological conditions of the retina such as age-related macular degeneration are associated with excess generation of reactive oxygen species (ROS), wherein PGC-1α affects these processes by promoting ROS detoxification; and ii) reduced levels of PGC-1α are observed in retinal disease models; and Roggia teaches: PGC-1α deficiency is related to aging phenotypes including dry AMD, and that upregulation of PGC-1α confers a protective benefit on RPE cells. Even further, a therapeutic approach targeting PGC-1α at the early stage of AMD may suppress the progression of this disease.
As such one of ordinary skill treating subjects suffering from dry AMD would have been motivated to determine whether the expression or activity levels of PGC-1α were reduced compared to normal levels (wherein “normal” levels are reasonably taken to be levels in a subject showing no measurable symptoms of dry AMD; i.e. an individual’s level of PGC-1α prior to the onset of dry AMD or an individual who does not display AMD; new Claims 61 – 63) because Egger teaches PGC-1α promotes ROS detoxification. Accordingly, reduced levels of PGC-1α (observed in the retinal disease models of Egger) would indicate higher levels of ROS and provide motivation to one of ordinary skill to administer the antioxidant fenofibrate, taught by del V Cano and Chiras to have a role in reducing ROS, a pathway strongly implicated in the pathogenesis of dry AMD (and moreover, taught to induce, through PPAR-α activation expression of antioxidant enzymes super oxide dismutase and glutathione peroxidase). Finally, it is noted that Egger’s teaching of determining levels of PGC-1α expression in various tissues would necessitate obtaining a sample from a subject to determine said levels as recited in step a) of instant Claim 38. Roggia strengthens the nexus between dry AMD and other aging phenotypes of RPE cells by establishing a relationship between PGC-1α deficiency and upregulation with aging phenotype and RPE protection, respectively. However, because the cited prior art references renders prima facie obvious administering the elected fibrate compound to the same patient population; i.e. subjects in need of treatment of dry AMD who have been determined to have a reduction in expression or activity levels of PGC-1α, any functional outcomes that accrue from said administration (e.g. inducing expression of PGC-1α in retinal pigment epithelial cells), would naturally flow, irrespective of whether the prior art was aware of said outcome.
Even further, Zhang teaches that the effects of various human feeders on growth of undifferentiated ESCs and two adult skin fibroblast cells lines established from abdominal skin biopsies supported prolonged growth over 30 weekly passages in culture. See p736, 3rd full par. Zhang studied ESCs from human foreskin and abdominal skin feeder cells for committed differentiation into RPE cells. Id. Cell replacement using functional RPE cells provides a hope to cure AMD that is caused by degeneration and dysfunction of the RPE. See p736, 2nd par. Abdominal fibroblasts can differentiate into RPE cells for therapies in treating retinal diseases, such as AMD. See p742, 2nd full par. Thus, using human skin derived RPE cells are more promising because they avoid heterologous contamination that was associated with mouse feeder layers. Overall and in view of Zhang a POSA would use a skin biopsy of abdominal skin feeder cells to obtain functional RPE for use as replacement therapy to treat dry AMD.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D. BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628