DETAILED ACTION Notice of Pre-AIA or AIA Status The present application is being examined under the pre-AIA first to invent provisions. Claim Status Claims 32-34 are currently pending. Priority Priority is acknowledged to 61/228,485 (7/24/2009). Information Disclosure Statement The information disclosure statement (IDS) submitted on 9/8/2023 has been considered. Claim Rejections - 35 USC § 112 , second paragraph 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 s 32-34 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 regards as the invention. Regarding claims 32-34 , the claims read in pertinent part, “selecting or identifying a compound capable of decreasing the phosphorylation of the E1α subunit of branched chain dehydrogenase enzyme protein complex … thereby increasing the enzymatic activity of said enzyme … .” Claim 32 lacks proper antecedent basis for the “said enzyme,” “the enzymatic activity,” and “said protein” limitations. The “branched chain dehydrogenase enzyme protein complex” is not a single enzyme/protein. To the contrary, this complex comprises multiple enzymes/proteins. See, for example, Harris (Harris et al., “Regulation of Branched-Chain α-Keto Acid Dehydrogenase Kinase Expression in Rat Liver.” Journal of Nutrition, 2001, 131(3), 841s-845s), especially “The branched-chain α-keto acid dehydrogenase complex” section starting on page 841S (“BCKDC … has three components: 1) a specific dehydrogenase … 2) a specific transacylase … and 3) [a] dihydrolipoamide dehydrogenase … .”). Further additional regulatory enzymes are bound to this complex as well including kinases like BDK. Id. Accordingly, it’s unclear which enzyme is being referred to or, alternatively, whether all enzymes are being referred to simultaneously. See MPEP § 2173.05(e) (“[I]f two different levers are recited earlier in the claim, the recitation of ‘said lever’ in the same or subsequent claim would be unclear where it is uncertain which of the two levers was intended.”). In addition, the specification fails to clarify this ambiguity. For instance, paragraphs [0009], [0010], [0018], etc. (referring to the corresponding PGPUB) discuss decreasing the phosphorylation of the E1α subunit rather than altering one of the enzymes of the complex itself such as the dehydrogenase. In addition, limitations from the specification are generally not read into the claims. See MPEP § 2111.01(II) ("It is improper to import claim limitations from the specification."). See also MPEP § 2173.01 ("We have cautioned against reading limitations into a claim from the preferred embodiment described in the specification, even if it is the only embodiment described, absent clear disclaimer in the specification … .”). Thus, even if, assuming arguendo , a particular embodiment was exemplified in the disclosure as preferred (or even most preferred), such a factual finding would not change the result. Furthermore, the later “baseline enzymatic activity” limitation in claim 32 would also be indefinite insofar as it is likewise unclear which enzymatic activity is being referred to (e.g., phosphatase, dehydrogenase, transacylase, etc. or combinations thereof). Moreover, it’s unclear whether the baseline is referring to a healthy individual (where the enzyme is active) or, alternatively, a person suffering from a disease where the activity has been compromised (e.g., MSUD). The baseline could be referring to different tissue specific levels of activation (e.g., highest in liver). Finally, this baseline could just be referring to just the inherent increase/decrease that happens to any enzyme upon phosphorylation/dephosphorylation as well (i.e., the language could simply be redundant). See MPEP § 2173.02(I) ("During examination, after applying the broadest reasonable interpretation to the claim, if the metes and bounds of the claimed invention are not clear, the claim is indefinite and should be rejected … For example, if the language of a claim, given its broadest reasonable interpretation, is such that a person of ordinary skill in the relevant art would read it with more than one reasonable interpretation, then a rejection under 35 U.S.C. § 112(b) or pre-AIA 35 U.S.C. § 112, second paragraph is appropriate."). Note too that claims 33 and 34 would also be indefinite by virtue of their claim dependencies. Regarding claim 33 , the claim additionally reads in pertinent part, “providing the E1α subunit … or a fragment thereof … that include phosphorylated Ser29 and Ser303 residues or fragment thereof … .” The second “fragment thereof” is unclear insofar as that limitation could be referring to the Ser303 residue, both the Ser29 and Ser303 residues, the first fragment that contains these serine residues, or the entire E1α fragment itself. See MPEP § 2173.02(I) ("During examination, after applying the broadest reasonable interpretation to the claim, if the metes and bounds of the claimed invention are not clear, the claim is indefinite and should be rejected … For example, if the language of a claim, given its broadest reasonable interpretation, is such that a person of ordinary skill in the relevant art would read it with more than one reasonable interpretation, then a rejection under 35 U.S.C. § 112(b) or pre-AIA 35 U.S.C. § 112, second paragraph is appropriate."). Finally, to the extent that fragments of the serine residues are permitted (e.g., serine residues with hydroxyl groups), it would be unclear how the selecting/identifying step for determining decreased phosphorylation at these positions could be accomplished (i.e., how do you measure the decrease in phosphorylation at positions Ser293 and Ser303 when one or both are not there). 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 32-34 are rejected under 35 U.S.C. § 101 because the claimed invention is directed to a law of nature and an abstract idea without significantly more. Question 1: Do the claim(s) fall into a statutory category of invention? Yes. The claims are directed to useful processes. 1-3 For example, claim 32 reads: 32. A method for screening for a compound useful for decreasing blood plasma levels of branched chain amino acids or branched chain alpha-ketoacid, comprising: selecting or identifying a compound capable of decreasing the phosphorylation of the E1α subunit of branched chain dehydrogenase enzyme protein complex at position Ser293 and Ser303; thereby increasing the enzymatic activity of said enzyme from baseline enzymatic activity. Question 2A (prongs 1 and 2): Are the claims directed to a judicial exception that is not integrated into a practical application? Yes. Claim 32 is drawn to both a natural law and an abstract idea. 4 For instance, claim 32 requires a “selecting” or “identifying” step that can be performed entirely in the mind or with the aid of pen and pencil. 5 Likewise, the “selecting” and “assessing” steps in claims 33 and 34, respectively, are also abstract ideas. Claim 32 is also drawn to the use of a natural law. 6 More specifically, Applicants are claiming the use of a natural correlation between the degree of phosphorylation of the E1α subunit of branched chain dehydrogenase enzyme protein complex at position ser293 and Ser303 and the overall activity of the enzyme complex relative to a baseline (see above). With respect to prong 2 of Question 2A, the guidance requires an evaluation as to whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. 7 Here, claim 32 does not require any additional steps other than the judicial exceptions. For instance, no “contacting step” is required. Compare claim 32 to claims 33 and 34 (where contacting steps are claimed). Accordingly, no integration has occurred for claim 32. 8 Claims 33 and 34, in contrast, both require further “contacting steps” where candidate compounds are contacted with target proteins/fragments (claim 33) or target cells (claim 34). However, these steps would represent mere data gathering activities expressed at a high level of generality thus would not integrate the claimed judicial exceptions either. 9 Question 2B: Do the claim(s) as a whole recite an inventive concept? No. In making this Step 2B determination, an evaluation must be performed as to whether there are specific limitations or elements recited in the claim, in addition to the JEs, that are not well-understood, routine, conventional activity in the field (and not written at a high level of generality) which would be indicative of an inventive concept. 10 As noted above, no additional limitations were added in claim 32. Accordingly, claim 32 does not claim an inventive concept. 11 Claims 33 and 34 add conventional screening steps such as contacting a candidate compound with a target or a target expressing cell. 12 However, mere conventional data gathering steps cannot make patent ineligible subject matter eligible. 13 Accordingly, claims 32-34 are rejected under 35 U.S.C. § 101. 1 See MPEP §§ 2106(I) and 2106.04(b)(II). 2 The Supreme Court has established a two-step framework for distinguishing patent eligible subject matter. See MPEP § 2106(I). In determining what concept the claim is "directed to," we first look to whether the claim recites any judicial exceptions, including laws of nature, natural phenomena, and/or abstract ideas. See MPEP § 2106.04, especially 2106.04(II)(A)(1) ("Step 2A, Prong One"). If it does, then we look to whether the claim recites additional elements that integrate the recited judicial exception into a practical application. See MPEP § 2106.04(II)(A)(2) ("Step 2A, Prong Two"). Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application (i.e., it is found to be "directed to" a judicial exception), do we then look to whether the claim contains an "inventive concept" sufficient to "transform" the claimed judicial exception into a patent-eligible application of the judicial exception. See MPEP § 2106.05 ("Step 2B"). 3 See 35 U.S.C. § 101 ("Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter … may obtain a patent therefor … ."). 4 See MPEP § 2106.04 (II)(A)(1) ("In Prong One examiners evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim."). See also MPEP § 2106.04 (a)-(c). 5 See MPEP § 2106.04(a) (“The enumerated groupings of abstract ideas are defined as … 3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion).”). See also MPEP § 2106.04(a)(2)(III)(a) (“Examples of claims that recite mental processes include: … a claim to identifying … which is a process that can be practically performed in the human mind.”). 6 See MPEP § 2106.04(b). 7 See MPEP §§ 2106.04(II)(A)(2) and 2106.04(d)(I). 8 See MPEP § 2106.04(II)(A)(2) ("if there are no additional claim elements besides the judicial exception, … that is insufficient to integrate the judicial exception into a practical application."). 9 See MPEP § 2106.05(g). 10 See MPEP § 2106.05. 11 See also MPEP § 2106.04 (II)(A)(2) ("For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception ... either at Prong Two or in Step 2B. If there are no additional elements in the claim, then it cannot be eligible."). 12 See Huser (Huser, J. “High-Throughput Screening in Drug Discovery” Wiley-VCN, 2006), chapter 4 showing that it was standard practice to contact a candidate compound with a target including an enzyme target. Further, Huser also teaches that it was standard practice to use cell-based screening assays as well. See, for example, Huser, section 4.1 (“The use of recombinant expression systems allowed one to screen chemical libraries against human receptors … to deliver end drugs improved selectivity and less side-effects … successful implementation in the HTS environment was largely due to the advent of fluorescence microplate readers with integrated liquid handling … Functional cell-based assays targeted towards a defined receptor provide a number of advantages over binding assays based on competition with labeled ligands. Binding assays typically provide only a limited dynamic range of the recorded signals whereas functional tests frequently utilize amplifying cellular signal transduction cascades … [using this technology] weak receptor activators with a low affinity or minimal efficacy can also be resolved.”). See also Huser, Preface (“Biological ‘trial and error’ testing of large collections of small molecules for a specific pharmacological effect is the classical route to discover novel lead compounds that subsequently serve as templates for futter optimization in medicinal chemistry programs … There are two general approaches for pharmacological assays: Assays measuring the binding of a candidate molecule to the target receptor (‘binding tests’) and assays monitoring the function of a target (or pathway) to visualize a possible modulation by small molecules.”). See also Huser, chapter 5, sections 5.4 and 5.5 (discussing use of oxidoreductases). See also page 95 (“We have developed an efficient process to allow the expression and purification of a wide variety of novel enzymes, of sufficient quantity and purity and with the required functional enzymatic activity to source HTS … Success is defined by the following criteria: did we successfully express and purify an active enzyme, did we develop an assay suitable for the screen and did we source the enzyme reagents to complete the screen? … [which include] (1) oxidoreductases (including reductases, dehydrogenases … .”). See also bottom of page 94 (“With automation, most modern HTS laboratories can complete the testing of a million compounds in less than 1 month … Although many would class binding assays for targets such as receptors or protein complexes ans biochemical, we focus exclusively on the prosecution of enzyme targets. These targets include … oxidoreductases … .”). Measuring blood plasma levels of BCAAs was also said to be routine in the art. See specification, page 12, paragraph [0031] (“The skilled artisan recognizes that plasma levels may be measured by standard methods in the art … .”). 13 See Mayo Collaborative Servs. v. Prometheus Labs., Inc. , 132 S. Ct. 1289, 1300 (2012) (“[S]imply appending conventional steps, specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patentable.”). See also CyberSource Corp. v. Retail Decisions, Inc. , 654 F.3d 1366, 1370 (“We have held that mere ‘[data-gathering] step[s] cannot make an otherwise nonstatutory claim statutory.”’). See also MPEP § 2106.05(g) (“Another consideration when determining whether a claim … recites significantly more in Step 2B is whether the additional elements add more than insignificant extra-solution activity to the judicial exception. The term ‘extra-solution activity’ can be understood as activities incidental to the primary process or product that are merely a nominal or tangential addition to the claim. Extra-solution activity includes both pre-solution and post-solution activity. An example of pre-solution activity is a step of gathering data … As explained by the Supreme Court, the addition of insignificant extra-solution activity does not amount to an inventive concept, particularly when the activity is well-understood or conventional … Below are examples of activities that the court have found to be insignificant extra-solution activity: Mere Data Gathering … .”_). 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 pre-AIA 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, 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 negated by the manner in which the invention was made. Claim 32-34 are rejected under pre- AIA 35 U.S.C. 103(a) as being unpatentable over Harris (Harris et al., “Regulation of Branched-Chain α-Keto Acid Dehydrogenase Kinase Expression in Rat Liver.” Journal of Nutrition, 2001, 131(3), 841s-845s) in further view of Huser (Huser , J. “High-Throughput Screening in Drug Discovery” Wiley-VCN, 2006 , chapters 4 and 5 ). Claims 32-34 are drawn to screening methods for decreasing the phosphorylation of the E1α subunit of the branched chain dehydrogenase enzyme protein complex. For instance, claim 32 reads, “A method for screening for a compound useful for decreasing blood plasma levels of branched chain amino acids or branched chain alpha-ketoacid, comprising selecting or identifying a compound capable of decreasing the phosphorylation of the E1α subunit of branched chain dehydrogenase enzyme protein complex at position Ser293 and Ser303; thereby increasing the enzymatic activity of said enzyme from baseline enzymatic activity.” Note that the limitation in claim 32 - 'thereby increasing the enzymatic activity of said enzyme from baseline' - is interpreted as an inherent property of the molecule selected/identified for decreasing phosphorylation or as the “intended use” of that selected/identified compound. Unlike dependent claims 33 and 34, claim 32 does not require a subsequent, affirmative “contacting step” to increase enzymatic activity. See also 35 U.S.C. § 112(b) section above. As to claims 32-34 , Harris (page 841S, abstract) teaches that excess branched-chain amino acids (BCAAs) are toxic in the body, and that the branched-chain α-keto acid dehydrogenase complex (BCKDC) is responsible for clearing this unwanted excess. Harris further teaches that BCKDC activity is controlled by a kinase (BDK), which inactivates the E1 component via phosphorylation of Ser 293 and Ser 303. Finally, Harris teaches that BDK itself is regulated by allosteric inhibitors, such as α-ketoisocaproate, which increase BCKDC activity by inducing dephosphorylation (page 842S, abstract). Therefore, a person of ordinary skill in the art would have found it prima facie obvious at the time the invention was made to use BDK inhibitors (e.g. α-ketoisocaproate) to treat diseases associated with toxic BCAA levels (page 841S, abstract), such as maple syrup urine disease (MSUD). A person of ordinary skill in the art would have had a reasonable expectation of success given that the inhibition of BDK directly removes the phosphorylation "off switch" (Ser 293/Ser 303 phosphorylation) which would maximize BCKDC activity to clear out the toxic unwanted BCAA excess. Note too that the disclosed BDK inhibitors (e.g., α-ketoisocaproate) would necessarily elevate BCKDC activity and thus inherently decrease blood plasma BCAA levels. For example, this increased BCKDC activity (by inhibiting BDK-mediated phosphorylation of the E1 subunit at Ser293 and Ser303) would necessarily trigger enhanced BCAA catabolism which would decrease the overall BCAA production (ultimately leading to decreased blood plasma levels). See In re Best , 562 F.2d 1252, 1255 (CCPA 1977) ("Where . . . the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product. Whether the rejection is based on 'inherency' under 35 U.S.C. § 102, on 'prima facie obviousness' under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products."). In addition, it would be prima facie obvious here to try to reduce these BCAA levels since elevated levels were known to be toxic (see above). Harris fails to teach a screening method per se for selecting/identifying compounds that can increase the activity of BCKDC. However, with respect to claim 32 , Huser teaches that it was standard practice in medicinal chemistry to screen for new therapeutic compounds (including lead optimization). See Huser, Preface (“Biological ‘trial and error’ testing of large collections of small molecules for a specific pharmacological effect is the classical route to discover novel lead compounds that subsequently serve as templates for futter optimization in medicinal chemistry programs … There are two general approaches for pharmacological assays: Assays measuring the binding of a candidate molecule to the target receptor (‘binding tests’) and assays monitoring the function of a target (or pathway) to visualize a possible modulation by small molecules.”). With respect to claims 33 and 34 , Huser teaches ‘binding assays” that would render obvious the use of candidate compounds and fragments of the E1α chain comprising at least 50 consecutive amino acids that include phosphorylated Ser293 and Ser 303. See, for example, Huser, Preface (“There are two general approaches for pharmacological assays: Assays measuring the binding of a candidate molecule to the target receptor (‘binding tests’) … .”). See also chapter 5. Huser also teaches the use of “cell- based” assays. See Huser, chapter 4 (“Functional Cell-based Assays for Targeted Lead Discovery in High-throughput Screening”). Accordingly, it would have been prima facie obvious to a person of ordinary skill in the art (POSITA) at the time the invention was made to use α-ketoisocaproate, as disclosed by Harris, as a lead compound for further screening. Huser teaches screening techniques were commonplace in medicinal chemistry for discovering more effective/safer treatments and thus it would be obvious to apply these techniques to look for better drugs for treating diseases associated with excess BCAAs, such as MSUD (e.g., by screening homologs or bioisosteres of α-ketoisocaproate and completely new lead compounds, etc.). Furthermore, a POSITA would have had a reasonable expectation of success, as homologs and isosteric compounds are generally known to possess similar properties, and standard high-throughput screening techniques were well-known for accelerating the discovery of effective drugs. See MPEP § 2144.09 (regarding the obviousness of making closely related structural derivatives); see also Harris, chapter 5, especially p. 99 (teaching the routine screening of enzymes, including phosphatases, for new modulators). A POSITA could also have readily monitored circulating BCAA levels here to determine the efficacy of the test compounds in animal models, patients, etc. Finally, it would have been prima facie obvious to a person of ordinary skill in the art (POSITA) at the time the invention was made to contact derivatives of α-ketoisocaproate (e.g., homologs, isosteric derivatives) with the E1α subunit of the branched chain dehydrogenase enzyme complex (or a fragment thereof comprising Ser29 and Ser303) to see whether such compounds could prevent phosphorylation and thus effectuate activation of the BCKDC to clear out unwanted toxic BCAAs. Further, a person of ordinary skill in the art would reasonably have expected to be successful for the reasons above (e.g., both in vitro and in vivo based assays were routinely used in screening and lead compounds and testing assays were already known). See also Huser, Preface (“Biological ‘trial and error’ testing of large collections of small molecules for a specific pharmacological effect is the classical route to discover novel lead compounds that subsequently serve as templates for futter optimization in medicinal chemistry programs … There are two general approaches for pharmacological assays: Assays measuring the binding of a candidate molecule to the target receptor (‘binding tests’) and assays monitoring the function of a target (or pathway) to visualize a possible modulation by small molecules.”). See also Huser, chapter 5, especially page 95 (“We have developed an efficient process to allow the expression and purification of a wide variety of novel enzymes, of sufficient quantity and purity and with the required functional enzymatic activity to source HTS … Success is defined by the following criteria: did we successfully express and purify an active enzyme, did we develop an assay suitable for the screen and did we source the enzyme reagents to complete the screen? … [which include] (1) oxidoreductases (including reductases, dehydrogenases … .”). See also sections 5.4 and 5.5 (discussing oxidoreductases). See also chapter 4 discussing cell-based assays. See also bottom of page 94 (“With automation, most modern HTS laboratories can complete the testing of a million compounds in less than 1 month … Although many would class binding assays for targets such as receptors or protein complexes ans biochemical, we focus exclusively on the prosecution of enzyme targets. 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