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 .
NOTE: Claim 5 was inadvertently added to the “generic” grouping in the election of species requirement. Claim 5 depends from claim 2, which was identified as a separate species, Species “i)”. Claims 17-19 stand withdrawn as being drawn to a non-elected invention, that of an in vitro assay.
Applicant’s election without traverse of Species “e)” “A method of identifying a compound that modulates Rel hydrolase/synthetase using a 3D structure represented by the full coordinates of Table 3 (p248, Rel-ppGpp-complex, closed form)” in the reply filed on 1/20/2026 is acknowledged.
Claims 2-6, 8-9, 11, 17-20, 24-25, 27, 29, 33, 35 and 37-40 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/20/2026. All other claims have been canceled.
Applicant’s request to include Species “i)” “a method to identify compounds modulating Rel hydrolase/synthetase activity by interactions with the binding site as recited in claim 2, since the binding site presented in claim 2 refers to the interaction of a compound with Rel of SEQ ID NO:1 in hydrolase active form, as provided by the 3D structure represented by the coordinates in Table 3, currently elected” (and associated claims 2 and 5) will be considered in the future, should Species “e)” be found allowable.
Claims 1, 7, 10, 12-16 are under examination to the extent they read on the elected species.
This application is a National Stage Application of PCT EP2020/059005, filed 3/30/2020. The examiner has reviewed all PCT and 371 related filing papers. 3/30/2020 is the effective filing date for the examined claims.
This application has published as US PG-Pub 2023/0128889 A1.
The drawings filed 9/28/2022 are suitable for examination.
The IDS filed 9/28/2022 has been entered and considered.
The preliminary amendment to the specification, filed 9/28/2022 has been entered.
The Sequence Listing filed 9/28/2022 and associated files have been entered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 7 is objected to because of the following informalities: The term “bona fide” is a phrase from Latin which should be italicized (“bona fide”) when used. Appropriate correction is required wherever used in the claims.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
A search of the term “Rel”, with respect to proteins, identified two unrelated sets of proteins. The “Rel Protein” is a designation applied to a protein in eukaryotic cells, that is a part of the NF-kappa-B complex. The “Rel Protein” is a designation also applied to a family of (p)ppGpp synthetase/hydrolase proteins in prokaryotes that are involved in the “stringent response” and help bacteria survive nutrient starvation (Google, downloaded 2026). The examiner notes that the second application appears to be the intended family of proteins, as illustrated by the recitation of the synthetase/ hydrolase activity and structural coordinates, and will interpret the term in this manner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7, 10, 12-16 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of structures represented by subsets of the coordinates of one of four separate Tables in claim 1, each Table representing a different 3-dimensional structure of Rel, bound or unbound to a given ligand, is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The Examiner notes while Applicant elected “a three-dimensional structure represented by the full coordinates of Table 3” the claim is not limited to this embodiment.
While the subsets all are members of the class of “structures representing portions of Rel proteins”, the Rel protein has more than one enzymatic activity, each carried out by a different portion of the protein, and has additional biological properties, such as antigenicity, not shared by all the encompassed subsets. The subsets are not required to have both enzymatic activities, thus subsets which have significantly different and non-overlapping three-dimensional structures, with differing biological/ enzymatic activities are encompassed by the claim: i.e. subsets that represent a polypeptide with synthetase activity, subsets which represent a polypeptide with hydrolase activity and other subsets which may represent a polypeptide without either enzymatic activity. Each different structure having a different enzymatic activity (or no activity) has a different use that flows from the enzymatic structure depending on the substructure of the Rel synthetase/ hydrolase represented. The subsets encompassed do not appear to be functionally equivalent. Subsets representing synthetase activity have a use in identifying compounds that modulate synthetase activity, while subsets representing hydrolase activity have a use in identifying compounds that modulate hydrolase activity. The use of subsets not clearly providing the structure for either activity is unclear within the context of the claimed method.
Amending the claim to clearly limit the claims to the elected Table and to clearly limit the subsets recited in the claims to structures representing the areas known to be required for both activities would likely overcome this rejection; alternatively deleting “subsets thereof” from each recitation in the claims may overcome this rejection.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claims 1, 7, 10, 12-16 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.
The metes and bounds of claim 1 are unclear, with respect to the steps required to identify a ligand that modulates one of two activities of the Rel protein. Claim 1 recites “the step of employing a three-dimensional structure represented by a set of atomic coordinates… and assessing a degree of fit….” however, the term “employing” does not set forth how the coordinates are to be used in any particular process, to identify any ligand or compound. The phrase encompasses any possible way to “employ” a set of coordinates, without direction or specificity. While breadth is not the same as indefiniteness, one of skill would not be apprised as to how Applicant intends the particular elected coordinate set is to be “employed” to achieve the desired goal. The claims are not limited to computer-implemented methods, nor do they provide any potential sets of candidate compounds/ ligands which could possibly be “fitted” to the three-dimensional structures in a computer-implemented docking process. The portion or structural region of the protein represented by the structural coordinates to which the ligand is to be fitted is not specified beyond the crystal structure recited in elected Table 3 “or a subset thereof.” The claim fails to set forth what the minimally required amount of coordinate data is for “a subset” of the coordinates of Table 3 to still be useful in the claimed method. Within the unspecified docking process, it is unclear at what point a “degree of fit” achieves the goal of identifying a compound that modulates the enzymatic activity, as no thresholds, reference data or ground truth information are provided for any type of comparison, nor is the fitted ligand tested in silico, in vitro or in vivo for any modulating ability. It is unclear if any degree of fit (0% to 100%) to any part of the recited structure results in the identification of a modulator of the enzymatic activities. The plain meaning of the term “modulates” encompasses any change, such as blocking, amplifying or reducing a given activity. The claim fails to provide any steps to determine what modulation is made by the structural docking/fitting as claimed. The term “assessing a degree of fit” does not set forth how the fit is assessed, or how the degree of fit is linked to any modulation of either recited activity. The claim fails to particularly point out and distinctly claim the necessary and sufficient steps and data required to carry out the desired process “identifying compounds that modulate Rel hydrolase and/or Rel synthetase”.
Regarding claim 7, the phrase "preferably wherein the conformational state… is the (P)ppGpp bounds conformational state…" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention, and are intended to limit the claim to that embodiment. See MPEP § 2173.05(d).
Claim 7 recites the limitation "the conformational state of Rel" in reference to claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 provides “a three-dimensional structure represented by a set of atomic coordinates presented in Table…3” but does not speak to conformational states of the protein.
The metes and bounds of claim 7 are further unclear with respect to the 3-D structures required to carry out the “comparing” of the Rel protein conformations. Claim 7 purports that the Rel protein structure to be compared with or without the ligand is the (P)ppGpp bound form of Rel (without ligand), “characterized by the atomic coordinates of Table 3” however it is unclear what aspects of the coordinates describe the conformations to be compared. It is unclear if any level of “conformational change” by the unspecified comparison truly represents the binding of a candidate to the (P)ppGpp bound Rel and truly represents that the candidate would modulate any Rel activity. No thresholds for the comparison or analysis of conformational change are present within the claim. No clear characterization of the intended conformational states to be compared are clearly provided. It is unclear if any modeled binding that results in some level of conformational change would indicate the ligand “to be a bona fide modulator of Rel hydrolase or Rel hydrolase and synthetase activity.” It is unclear at what level of ligand binding to the (P)ppGpp bound form of Rel would indicate a bona fide modulator of either or both activities.
Claim 10 recites the limitation "upon binding with one or more of said Rel amino acid residues" in reference to claim 7. There is insufficient antecedent basis for this limitation in the claim. Claim 7 does not recite particular amino acid residues to which a ligand is compared to assess a binding or degree of fit. Claim 1, from which claim 7 depends does not set forth any particular amino acids to which the ligand is assessed for binding/ degree of fit.
The metes and bounds of claim 10 are unclear with respect to the identification of the ligand as a Rel hydrolase inhibitor. Claim 10 sets forth that if the conformational state of the (P)ppGpp bound Rel stabilizes in an “open state” in the presence of the candidate, that candidate is identified as a Rel hydrolase inhibitor. The metes and bounds of “stabilized in an open state” are entirely unclear with respect to the steps set forth in claims 1 and 7 from which claim 10 depends. It is unclear at what step the “stabilization” is characterized, nor is it clear how to identify such a stabilization. It is unclear at what point in a docking simulation a binding of a ligand to the protein is considered to be “stabilized.” The “open state” of the bound (P)ppGpp bound Rel is not clearly set forth or described by the claim. The claim fails to particularly point out and distinctly claim how the parameters of “assessing a degree of fit of a candidate compound” could provide the required stabilization information.
The metes and bounds of claim 12 are unclear with respect to how the candidate is to be tested for the given activity. It is unclear if this is intended to be a further part of the modeling and “assessing degree of fit” of claim 1, or whether this represents in vitro testing activity. The candidate compound is not clearly provided or synthesized such that is could be tested. While breadth of the claim is not equal to indefiniteness, one of skill would not be apprised as to the particular steps Applicant intended to be carried out to identify the modulation of the synthetase or hydrolase activity.
The metes and bounds of claim 13 are unclear with respect to the computer-implementation of the method of claim 1. Step a) of claim 1 is directed to “generating a three-dimensional structure of said atomic coordinates or subset thereof.” This step fails to set forth how the structure is generated or what it is intended to look like. In the art of 3D modeling of proteins, a multiplicity of display options exists for identification of protein conformation, identifying active sites, or comparison with other structures. It is unclear what structures were intended by Applicant to be used to carry out the subsequent steps of “fitting” and “selecting.” The metes and bounds of step b) are unclear with respect to how Applicant intended the fitting to be carried out in a computer modeling process. Neither claim 13 nor claim 1 actually provide any candidate compound of any particular structure which is to be fitted to the elected form of the Rel protein. It is unclear if this process requires the co-crystallization of each candidate with the elected form of the Rel protein, followed by obtaining the crystallization coordinates, followed by some comparison between the co-crystal structure and the elected structure and coordinates, or whether a representation of the candidate compound is obtained and fitted in silico to the structure generated in step a) in a conventional docking process, or whether some other interpretation was intended. The metes and bounds of the term “by computer modeling” fails to particularly point out and distinctly claim what Applicant considers their invention, as this phrase merely sets forth that a computer model is somehow involved. It is not the direction of a particular modeling or docking process carried out on a particular 3D structure, with and without a 3D representation of a candidate compound, followed by energetic modeling. Step c) indicates that the selection of a candidate is based on “energetically favorable interactions with the structure of step a) without carrying out any calculation of a change in free energy, or the identification of any favorable, or unfavorable interactions between the two representations. The term “energetically favorable interactions” in claim 13 is a relative term which renders the claim indefinite. The term “energetically favorable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is further unclear that any or all “favorable” interactions lead to the identification of an actual modulator of Rel synthetase and/or hydrolase activity as required by claim 1.
The metes and bounds of claim 14 are unclear with respect to how the superimposition between the 3D structure representing the elected Rel protein form, and the candidate compound are to be carried out. No structure of a candidate compound is clearly provided by claims 1, or 13. This claim is written using results-based language but fails to particularly set forth how the result is to be obtained. It is unclear how the superimposed fitting is assessed for any “energetically favorable” interactions as required by claim 13. The recitation of superimposition doesn’t specify how it is to be carried out in a way that satisfies all the requirements of claims 13 and 1, including assessing the degree of fit.
The metes and bounds of claim 15 are unclear with respect to how, in particular, the “docking modeling” is to be carried out in the method of claim 13. The claim fails to particularly point out and distinctly claim how any structure of the candidate compound is fitted to the elected structure of the Rel protein, and compared, in a “docking modeling” environment, to the unfitted protein, to identify any “energetically favorable interactions” or any modulatory activity. The claim fails to particularly point out and distinctly claim the steps performed by the “docking modeling” to achieve the desired result. Merely reciting a branch of information analysis fails to particularly point out what Applicant considers their invention. This claim is written using results-based language ans fails to particularly set forth how the result is to be obtained.
The metes and bounds of claim 16 are unclear with respect to how the “binding” of any structural representation of a candidate compound to an amino acid residue of the structural representation of the elected Rel protein is identified. This claim is written using results-based language but fails to particularly set forth how the result is to be obtained. Claim 13 does not identify any particular binding between the representation of the candidate and a specific amino acid of the representation of elected Rel protein. Claim 13 identifies “energetically favorable interactions” between the structure of the candidate and the structure generated in step a) of the elected Rel protein. The terms “energetically favorable interactions” and “binding” are not necessarily interchangeable designations, with or without “steric interference”.
While claims are read in light of the specification, limitations from the specification cannot be read into the claims. MPEP 2111, 2173.02. See also In re Prater, Superguide Corp. v DirecTV Enterprises, Inc.
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 1, 7, 10, 12-16 is/are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea of mental steps, mathematic concepts, organizing human activity, or a natural law without significantly more.
Applicant is directed to MPEP 2106 and the Federal Register notice (FR89, no 137 (7/17/2024) p 58128-58138) for the most current and complete guidelines in the analysis of patent- eligible subject matter. The current MPEP is the primary source for the USPTO’s patent eligibility guidance.
With respect to step (1): YES, the claims are drawn to statutory categories: processes.
With respect to step (2A) (1): YES, the claims recite an abstract idea, law of nature and/or natural phenomenon. The claims explicitly recite elements that, individually and in combination, constitute one or more judicial exceptions (JE).
Mathematic concepts, Mental Processes or Elements in Addition (EIA) in the claim(s) include:
1. (Original) A method for identifying compounds that modulate Rel hydrolase and/or Rel synthetase activity comprising the step of
(Preamble, identifying the claim as a method claim, and the goal of the method.)
employing a three-dimensional structure represented by a set of atomic coordinates presented in Table 1, 2, 3, or 4 or a subset thereof, or atomic coordinates which deviate from those in Table 1, 2, 3, or 4, or a subset thereof, by a root mean square deviation (RMSD) of residue over protein backbone atoms by no more than 3 A, and
(Mental step of observing a 3D structure represented by the coordinates, or a portion thereof. MPEP 2106.04(a)(2) Section III.)
assessing the degree of fit of a candidate compound to said three-dimensional protein structure of Rel.
(Mental step of observation, analysis and making a judgement as to whether a representation of the candidate compound could fit to some degree to the three-dimensional structure of the previous step. MPEP 2106.04(a)(2) Section III.)
7. (Previously presented) The method according to claim 1, further comprising comparing the conformational state of Rel with or without said candidate compound binding to Rel, wherein a change in conformational state is indicative for the candidate compound to be a bona fide modulator of Rel hydrolase or Rel hydrolase and synthetase activity, preferably wherein the conformational state of Rel without candidate compound binding is the (P)ppGpp bound conformational state characterized by the atomic coordinates of Table 3.
(Mental step of comparison of two structural representations, and making a judgement as to whether a change has occurred in the conformation of Rel. MPEP 2106.04(a)(2) Section III.)
10. (Original) The method according to claim 7, wherein the candidate compound is considered a Rel hydrolase inhibitor when upon binding with one or more of said Rel amino acid residues, Rel is stabilized in an open state.
(Mental step of observing the state of the structure of the Rel protein fitted with the structure of the candidate, and making a judgement as to whether the state is open or not MPEP 2106.04(a)(2) Section III.)
12. (Previously presented) The method according to claim 1, further comprising testing of the ability of the candidate compounds for modulating Rel synthetase and/or Rel hydrolase activity.
(EIA- testing the unspecified compound for “modulating” in an unspecified manner. A step of Extra-solution activity. MPEP 2106.05(g).)
13. (Previously presented) The method according to claim 1, which is a computer- implemented method, said computer comprising an inputting device, a processor, a user interface, and an outputting device, wherein said method comprises the steps of:
(Preamble limiting the method to computer implementation, and an EIA, a general-purpose computer system.)
a) generating a three-dimensional structure of said atomic coordinates, or said subset thereof;
(Mental step of considering the atomic coordinates and creating a dimensional drawing or structural representation of the coordinates, using the computer as a tool/ or in a computing environment. MPEP 2106.04(a)(2) Section III.)
b) fitting the structure of step a) with the structure of a candidate compound by computational modeling; and
(Mental step of observing the structure of the candidate, and making a judgement as to whether the candidate structure fits to the generated structure, using the computer as a tool, or in a computing environment. MPEP 2106.04(a)(2) Section III.)
c) selecting a candidate compound that possesses energetically favorable interactions with the structure of step a).
(Mental step of data identification and selection when a compound meets a condition. MPEP 2106.04(a)(2) Section III. Alternatively, a mathematic concept of calculating changes in free energy between the fitted and unfitted structural representations. MPEP 2106.04(a)(2) Section I.)
14. (Original) The method according to claim 13, wherein said fitting comprises superimposing the structure of step a) with the structure of said candidate compound.
(Mental step of observation of the structures overlapping in 3D space, using a computer as a tool or in a computing environment. MPEP 2106.04(a)(2) Section III.)
15. (Previously presented) The method according to claim 13, wherein said modeling comprises docking modeling.
(Mental step of taking the structure of the candidate and inputting it into a generic docking analysis to observe whether any degree of fit, or “energetically favorable” interactions exist. MPEP 2106.04(a)(2) Section III.)
16. (Previously presented) The method according to claim 13, wherein said candidate compound of step c) can bind to at least 1 amino acid residue of the structure of step a) without steric interference.
(Mental step of observing the fitting of the candidate to the Rel structure, and making a judgement as to whether the candidate binds to an amino acid, and making a judgement as to whether any 3D steric interference would be present. MPEP 2106.04(a)(2) Section III.)
With respect to step 2A (2): NO, the claims do not integrate any JE into a practical application (MPEP 2106.04(d)). The claimed additional elements are analyzed alone, or in combination to determine if the JE is integrated into a practical application (MPEP 2106.05(a-c, e, f and h)).
Claims 1, 7, and 10 do not set forth any additional elements. Therefore, the JE is not integrated into a practical application for those claims.
Claim(s) 12 recite(s) the additional element (EIA) of generically-stated testing of the unspecified compound for enzymatic activity.
The EIA do not provide meaningful limits to the claim, are tangential to the judicial exception identified in claim 1, and are therefore extra-solution activity. MPEP 2106.05(g). 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.
Generically-stated testing for enzymatic activity after the inventive primary process of determining a degree of fit between a candidate and a structure represents a confirmation of the result of a degree of fit, and is only nominally related to the actual invention. The testing has no particular steps or aspects. In contrast to Diehr, where the calculations carried out in the claim directly affected when the additional element of “open the press” is to be carried out, the steps making up the JE of claim 1 do not have any significant link to how the testing is carried out in claim 12.
Claim(s) 13 recite(s) the additional non-abstract element (EIA) of a general-purpose computer system or parts thereof.
The EIA do not provide any details of how specific structures of the computer elements are used to implement the JE. The claims require nothing more than a general-purpose computer to perform the functions that constitute the judicial exceptions. The computer elements of the claims do not provide improvements to the functioning of the computer itself (as in DDR Holdings, LLC v. Hotels.com LP); they do not provide improvements to any other technology or technical field (as in Diamond v. Diehr); nor do they utilize a particular machine (as in Eibel Process Co. v. Minn. & Ont. Paper Co.). Hence, these are mere instructions to apply the JE using a computer, and therefore the claim does not recite integrate that JE into a practical application.
Dependent claim(s) 7, 10, 13-16 recite(s) an abstract limitation to the JE reciting additional mathematic concepts, or mental processes. Additional abstract limitations cannot provide a practical application of the JE as they are a part of that JE.
In combination, the limitations of data gathering, for the purpose of carrying out the JE, using a general-purpose computer merely provide extra-solution activity, and fail to integrate the JE into a practical application.
With respect to step 2B: NO, the claims do not provide a specific inventive concept. The judicial exception alone cannot provide that inventive concept or practical application (MPEP 2106.05). The additional elements were considered individually and in combination to determine if they provide significantly more than the judicial exception. (MPEP 2106.05.A i-vi).
Claims 1, 7, and 10 do not set forth any additional elements. As such these claims do not provide a specific inventive concept.
With respect to claim(s) 12: The limitation(s) identified above as non-abstract elements (EIA) related to the extra-solution activity (MPEP 2106.05(g)):
Gratani (2017) tests candidate compounds in vitro to determine modulation of enzymatic activity of the Rel protein.
Fang (2018) tests candidate compounds in vitro to determine modulation of enzymatic activity of Rel protein.
Mechold (2002) tests candidate compounds in vitro to determine modulation of enzymatic activity of Rel protein, and subunits of Rel protein.
As such, the prior art supports the assertion that the testing of candidates for modulation of Rel activity in vitro was routine, well understood and conventional.
Additionally, page 38 of the specification provides routine, well understood and conventional means for performing the testing, including a citation of Ou et al. (2018).
MPEP 2106.05(g) sets forth the considerations as to whether an element in addition to the JE (EIA) represents extrasolution activity:
(1) Whether the extra-solution limitation is well known. (See Bilski v. Kappos, Flook, Intellectual Ventures I LLC v. Erie Indem. Co.): The limitation has been shown to be well known in the prior art, for the protein at hand (Rel (p)ppGpp).
(2) Whether the limitation is significant (i.e. it imposes meaningful limits on the claim such that it is not nominally or tangentially related to the invention). (See Ultramercial, Inc. v. Hulu, LLC, Apple, Inc. v. Ameranth, Inc.) The identified JE does not have any particular link to carrying out the testing, is generically stated, and is carried out no matter the results of the JE.
(3) Whether the limitation amounts to necessary data gathering and outputting, (i.e., all uses of the recited judicial exception require such data gathering or data output). (See Mayo, OIP Techs., Inc. v. Amazon.com, Inc.).
With respect to claim(s) 13: the limitations identified above as non-abstract elements (EIA) related to general-purpose computer systems do not rise to the level of significantly more than the judicial exception.
Wexselblatt (2012; PTO-1449, ISR210), van Nerom (2019; PTO-1449, ISR210), Pagdala (2017; PTO-1449, ISR210) each disclose computer systems or computing elements which meet the BRI of the claimed computer system or computer system elements, comprising input, output/ display, a processor, and memory.
As such, the prior art recognizes that these computing elements are routine, well understood and conventional in the art.
The specification, at pages 40 127-128 et al, discloses the use of routine general-purpose computers for carrying out the invention.
These elements do not improve the functioning of the computer itself, or comprise an improvement to any other technical field (Trading Technologies Int’l v IBG, TLI Communications). They do not require or set forth a particular machine (Ultramercial v. Hulu, LLC., Alice Corp. Pty. Ltd v. CLS Bank Int’l), they do not effect a transformation of matter, nor do they provide an unconventional step. Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception are insufficient to provide significantly more (as discussed in Alice Corp., CyberSource v. Retail Decisions, Parker v. Flook, Versata Development Group v. SAP America).
Dependent claim(s) 7, 10, 13-16 each recite a limitation requiring additional mathematic concepts or mental processes. Additional abstract limitations cannot provide significantly more than the JE as they are a part of that JE (MPEP 2106.05).
In combination, the data gathering steps providing the information required to be acted upon by the JE, performed in a generic computer or generic computing environment fail to rise to the level of significantly more than that JE. The data gathering steps provide the data for the JE, which is carried out by the general-purpose computers. No non-routine step or element has clearly been identified.
The claims have all been examined to identify the presence of one or more judicial exceptions. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether the additional limitations integrate the judicial exception into a practical application. Each additional limitation in the claims has been addressed, alone and in combination, to determine whether those additional limitations provide an inventive concept which provides significantly more than those exceptions. For these reasons, the claims, when the limitations are considered individually and as a whole, are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
New citations:
Gratani, F. L. et al. (2018) Regulation of the opposing (p)ppGpp synthetase and hydrolase activities in a bifunctional RelA/SpoT homologue from Staphylococcus aureus. PLOS Genetics, 14(7) e1007514, 20 pages.
Fang, M. et al. (2018) Regulation of stringent factor by branched chain amino acids. PNAS, 115(25) p6446-6451.
Mechold, U. et al. (2002) Intramolecular Regulation of the Opposing (p)ppGpp Catalytic Activities of Relseq, the Rel/Spo Enzyme from Streptococcus equisimilis. Journal of Bacteriology, 184(11) p2878-2888.
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.
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.
Claim(s) 1, 7, 10, 12-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Nerom (2019) in view of Pagadala (2017).
Van Nerom et al. (2019) The Rel stringent factor from Thermus thermophilus: crystallization and X-ray analysis. Structural Biology Communications, vol 75: 561-569. PTO-1449.
Pagadala et al. (2017) Software for molecular docking: a review. Biophysiology Reviews vol 9:91-102. PTO-1449.
The claims are drawn to methods of using a 3D structural representation of a Rel protein, represented by a set of X-ray crystallography coordinates or subsets thereof, to identify modulators of one or more activities of the Rel protein, by assessing the “degree of fit” of a ligand to the 3D representation. Applicant has elected the full set of coordinates of Table 3.
The Examiner notes that while Van Nerom lists one or more inventors of the application, the inventorship is not the same, therefore this is considered to be “by another.” Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). (MPEP 2153.01(a)).
Van Nerom provides the X-ray coordinates of three crystal forms of “a bifunctional Rel RSH protein from Thermus thermophilus.” P562. At least one set of coordinates represents the full length Rel protein bound to (p)ppGpp. (section 2.6, p564-565, section 3.4 p566-567). Subsets thereof are also disclosed. The 3D representation of the coordinates is provided in section 2.10, section 3.4, and Figure 3b. Various computer programs were used in creating the 3D representation of the coordinates, including MATTHEWS_COEFF, MOLREP, Phaser, and unspecified “automated model building.” The Rel RSH protein studied by Van Nerom has both hydrolase and synthetase activities.
Van Nerom notes that:
“In the bacterial cell, (p)ppGpp levels are regulated by the concerted opposing activities of RSH (RelA/ SpoT homologue) enzymes that can transfer a pyrophosphate group of ATP to the 3' position of GDP (or GTP) or remove the 3' pyrophosphate moiety from (p)ppGpp.”
These activities are important to the survival of bacteria, in the “stringent response” which is the reaction of bacteria to nutrient starvation. The stringent response affects bacterial processes including transcription, translation and DNA replication. Identification of modulators of these activities could identify useful antibacterial or antibiotic ligands.
Van Nerom identifies the regions of the Rel protein that have the hydrolase activity, and the synthetase activity, set forth in Section 3.3, p566.
“The N-terminal region of long Rel enzymes harbours two catalytic domains with opposing activities. In Rel-NTD-Ti the HD domain (residues 1-158) has a pyrophospho-hydrolase activity
and is involved in the cellular degradation of (p)ppGpp, whereas the SYN domain (residues 198-355) binds GTP/GDP and ATP to synthesize (p)ppGpp. It has long been speculated that the nucleotide substrates of the enzyme dictate the conformational arrangement of the domains in the NTD region based on the structures of Rel-NTD-Seq. However, these structures failed to capture the full regulatory mechanism that involves allosteric triggering of metal ion-catalysed hydrolysis and a strong protein-dynamics component.”
Van Nerom does not specifically “employ” the generated 3D representation of Fig 3B to “assess the degree of fit” of a candidate compound, for identifying a modulator of Rel.
In the field of modeling 3D representations of proteins, based on coordinates, to identify modulators of the activity of a protein, Pagadala provides a multiplicity of options for generating 3D models using various types of data characterizing the protein, and a multiplicity of docking programs which assess the “degree of fit” of a candidate ligand to the modeled protein.
“Molecular docking methodology explores the behavior of small molecules in the binding site of a target protein. As more protein structures are determined experimentally using X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, molecular docking is increasingly used as a tool in drug discove1y. Docking against homology modeled targets also becomes possible for proteins whose structures are not known. With the docking strategies, the
druggability of the compounds and their specificity against a particular target can be calculated for further lead optimization processes. Molecular docking programs perform a search algorithm in which the conformation of the ligand is evaluated recursively until the convergence to the minimum energy is reached. Finally, an affinity scoring function, ΔG [U total in kcal/mol], is employed to rank the candidate poses as the sum of the electrostatic and van der Waals energies. The driving forces for these specific interactions in biological systems aim toward complementarities between the shape and electrostatics of the binding site surfaces and the ligand or substrate.” (Abstract).
“Over the last two decades, more than 60 different docking tools and programs have been developed for both academic and commercial use...” P92.
The independent claim does not set forth, specifically, how the degree of fit is calculated.
Pagadala notes that “degree of fit” is analyzed in most docking simulations, and is represented by a docking score.
“The sum of all these interactions is approximated by a docking score, which represents potentiality of binding.” P91.
“Consequently, these flexible docking algorithms not only predict the binding mode of a molecule more accurately than rigid body algorithms, but also its binding affinity relative to other compounds (Verkhivker et al. 2000).”
Pagadala reviews differing strategies used by the various docking tools, including a) incremental construction approaches, b) shape-based algorithms (superimposition), c) genetic algorithms, d) systematic search techniques, and e) Monte Carlo simulations. Docking scores generated by these tools can include scoring or calculating binding affinity, calculating changes in free energy (ΔG), calculating the accuracy compared to a ground truth structure, scoring electrostatic/ atomic solvation interactions, scoring and/or ranking the lowest-energy conformations, using scores of shape complementarity, scoring complimentary physical-chemistry features, scoring or calculating hydrophobic complementarity, Coulombic potentials, Lennard-Jones potential scores, volumetrics, Gaussian shape fitting functions, induced fit algorithms, and many other metrics. All of these appear to meet the BRI of “assessing the degree of fit.”
“Among these programs, AutoDock Vina, GOLD, and MOE-Dock predicted top ranking poses with best scores. GOLD and LeDock were able to identify the correct ligand binding poses. Both Glide (XP) and GOLD predict the poses consistently with a 90.0% accuracy (Wang et al 2016). It was also shown that GOLD produced higher enrichment factors than Glide in a virtual screening trial against Factor Xa, whereas Glide outperformed GOLD against the same target in a similar virtual screening trial. Overall, it was reported recently that these docking programs are able to predict experimental poses with root-mean-squared deviations (RMSDs) averaging from 1.5 to 2 Å (Bissantz et al. 2000;
Dixon 1997).” P92
In KSR Int 'l v. Teleflex, the Supreme Court, in rejecting the rigid application of the teaching, suggestion, and motivation test by the Federal Circuit, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Applying the KSR standard of obviousness to Van Norem and Pagadala, the Examiner concluded that the combination of the employing the x-ray coordinates of the Rel protein of Van Norme, and the 3D representation of those coordinates in a molecular docking process to assess the degree of fit of a candidate ligand as disclosed by Pagadala, represents a combination of known elements which yield the predictable result of a computer-implemented process to score candidate modulators of Rel protein in a 3D modeling environment, which identifies potential modulators of one or more activities of that protein. Van Norem provides the coordinates and an initial 3D structure representation, and provides information regarding where in the Rel protein a ligand may bind to modulate either enzymatic activity. One of skill in the art of bacteriology would have been interested in identifying modulators of Rel, as they could lead to the identification of new antibiotic or antibacterial compounds. Pagadala provides a multiplicity of computer-based docking programs which are able to assess the degree of fit of any candidate ligand to the 3D modeled protein. Pagadala described how each program functions, and how the programs performed in certain validation experiments. One of skill in the art of 3D modeling of proteins would have looked to Pagadala to determine which program best meets the requirement to calculate a degree of fit of a candidate ligand to a 3D representation of a protein. Such a combination is merely a "predictable use of prior art elements according to their established functions." KSR Int’l 7, 127 S. Ct. at 1740.
With respect to claim 7, Van Nerom provides Rel conformations bound to (p)ppGpp, and atomic coordinates meeting Table 3, and subsets thereof. Pagadala provides programs which can model, compare and score different conformational poses of a protein, with and without the ligand.
With respect to claim 10, Van Nerom provides how stabilization was assessed for both hydrolase and synthetase activity.
With respect to claim 12, Van Nerom further provides in vitro assays for assessing ppGpp synthesis and hydrolysis by purified Rel proteins. (Section 2.6, p564-565).
With respect to claim 13, Pagadala provides the computer-based modeling, using computers meeting the requirements. The programs identified by Pagadala can perform the generation of the 3D structure based on x-ray coordinates, fit candidate ligands to the modeled protein, and score/ select a candidate for “favorable energetic interactions.”
With respect to claims 14-15, Pagadala provides both superimposition/ rigid body modeling and flexible docking programs.
With respect to claim 16, Van Nerom provides some amino acid residues important for enzymatic activity, which would have been important in the 3D modeling of the candidate: protein interaction.
Claim(s) 1, 7, 10, 12-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Singal (2017) in view of Pagadala (2017).
Singal et al. (2017) Crystallographic and solution structure of the N-terminal domain of the Rel protein from Mycobacterium tuberculosis. FEBS Letters S91, p2323-2337.
Pagadala et al. (2017) Software for molecular docking: a review. Biophysiology Reviews vol 9:91-102. PTO-1449.
The claims are drawn to methods of using a 3D structural representation of a Rel protein, represented by a set of X-ray crystallography coordinates or subsets thereof, to identify modulators of one or more activities of the Rel protein, by assessing the “degree of fit” of a ligand to the 3D representation. Applicant has elected the full set of coordinates of Table 3.
Singal is directed to the analysis of crystal structures of the M tuberculosis bifunctional enzyme mtRel, with both synthetase and hydrolase activities.
“Modulation of intracellular guanosine 3' ,5'-bispyrophosphate ((p)ppGpp) level, the effector of the stringent response, is crucial for survival as well as optimal growth of prokaryotes and, thus, for bacterial pathogenesis and dormancy. In Mycohacterium tuberculosis (Mtb), (p)ppGpp synthesis and degradation are carried out by the bifunctional enzyme MtRel, which consists of 738 residues, including an N-terminal hydrolase- and synthetase-domain (N-terminal domain or NTD) and a C-terminus with a ribosome-binding site. Here, we present the first crystallographic structure of the enzymatically active MtRel NTD determined at 3.7 A resolution. The structure provides insights into the residues of MtRel NTD responsible for nucleotide binding. Small-angle X-ray scattering experiments were performed to investigate the dimeric state of the MtRel NTD and possible substrate-dependent structural alterations.” (Abstract).
Singal provides 3D representations of x-ray coordinates of the Rel protein of M tuberculosis, which appear to meet the BRI of the condition that the coordinates be those of the recited Tables 1-4, or subsets thereof, or those that deviate from Tables 1-4 by no more than 3Å or subsets thereof. (p2325-2326) “The atomic coordinates and structure factors have been deposited in the Protein Data Bank (PDB ID: 5XnX).” (P2325) The crystal structure is discussed beginning at p2327, col 2.
Singal utilizes the x-ray coordinate data to generate 3D representations of the MtRelNTD protein having hydrolase and synthetase activities, in a computer modeling process. (p2327-2329, and Fig 4). Regions of the structure involved in hydrolase and synthetase activity are identified, as well as a binding pocket for (p)ppGpp. Singal notes that based on the high level of ASP and HIS residues in the hydrolase domain requires the coordination of divalent metal ions for stability of conformation. Singal identifies particular amino acid residues critical for the synthase and hydrolase domain activities. (p2329). Singal identifies different conformational poses of Rel, beginning at p2331. Singal identifies a “stabilized” conformational state of the protein at pages 2331-2332.
Singal does not specifically use the 3D representation of the MtRelNTD protein to assess a degree of fit of a candidate ligand.
In the field of modeling 3D representations of proteins, based on coordinates, to identify modulators of the activity of a protein, Pagadala provides a multiplicity of options for generating 3D models using various types of data characterizing the protein, and a multiplicity of docking programs which assess the “degree of fit” of a candidate ligand to the modeled protein.
“Molecular docking methodology explores the behavior of small molecules in the binding site of a target protein. As more protein structures are determined experimentally using X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, molecular docking is increasingly used as a tool in drug discove1y. Docking against homology modeled targets also becomes possible for proteins whose structures are not known. With the docking strategies, the
druggability of the compounds and their specificity against a particular target can be calculated for further lead optimization processes. Molecular docking programs perform a search algorithm in which the conformation of the ligand is evaluated recursively until the convergence to the minimum energy is reached. Finally, an affinity scoring function, ΔG [U total in kcal/mol], is employed to rank the candidate poses as the sum of the electrostatic and van der Waals energies. The driving forces for these specific interactions in biological systems aim toward complementarities between the shape and electrostatics of the binding site surfaces and the ligand or substrate.” (Abstract).
“Over the last two decades, more than 60 different docking tools and programs have been developed for both academic and commercial use...” P92.
The independent claim does not set forth, specifically, how the degree of fit is calculated.
Pagadala notes that “degree of fit” is analyzed in most docking simulations, and is represented by a docking score.
“The sum of all these interactions is approximated by a docking score, which represents potentiality of binding.” P91.
“Consequently, these flexible docking algorithms not only predict the binding mode of a molecule more accurately than rigid body algorithms, but also its binding affinity relative to other compounds (Verkhivker et al. 2000).”
Pagadala reviews differing strategies used by the various docking tools, including a) incremental construction approaches, b) shape-based algorithms (superimposition), c) genetic algorithms, d) systematic search techniques, and e) Monte Carlo simulations. Docking scores generated by these tools can include scoring or calculating binding affinity, calculating changes in free energy (ΔG), calculating the accuracy compared to a ground truth structure, scoring electrostatic/ atomic solvation interactions, scoring and/or ranking the lowest-energy conformations, using scores of shape complementarity, scoring complimentary physical-chemistry features, scoring or calculating hydrophobic complementarity, Coulombic potentials, Lennard-Jones potential scores, volumetrics, Gaussian shape fitting functions, induced fit algorithms, and many other metrics. All of these appear to meet the BRI of “assessing the degree of fit.”
“Among these programs, AutoDock Vina, GOLD, and MOE-Dock predicted top ranking poses with best scores. GOLD and LeDock were able to identify the correct ligand binding poses. Both Glide (XP) and GOLD predict the poses consistently with a 90.0% accuracy (Wang et al 2016). It was also shown that GOLD produced higher enrichment factors than Glide in a virtual screening trial against Factor Xa, whereas Glide outperformed GOLD against the same target in a similar virtual screening trial. Overall, it was reported recently that these docking programs are able to predict experimental poses with root-mean-squared deviations (RMSDs) averaging from 1.5 to 2 Å (Bissantz et al. 2000;
Dixon 1997).” P92
In KSR Int 'l v. Teleflex, the Supreme Court, in rejecting the rigid application of the teaching, suggestion, and motivation test by the Federal Circuit, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
Applying the KSR standard of obviousness to Singal and Pagadala, the Examiner concluded that the combination of the employing the x-ray coordinates of the Rel protein of Singal, and the 3D representation of those coordinates in a molecular docking process to assess the degree of fit of a candidate ligand as disclosed by Pagadala, represents a combination of known elements which yield the predictable result of a computer-implemented process to score candidate modulators of Rel protein in a 3D modeling environment, which identifies potential modulators of one or more activities of that protein. Singal provides the coordinates and an initial 3D structure representation, and provides information regarding where in the Rel protein a ligand may bind to modulate either enzymatic activity. One of skill in the art of bacteriology would have been interested in identifying modulators of Rel, as they could lead to the identification of new antibiotic or antibacterial compounds. Pagadala provides a multiplicity of computer-based docking programs which are able to assess the degree of fit of any candidate ligand to the 3D modeled protein. Pagadala described how each program functions, and how the programs performed in certain validation experiments. One of skill in the art of 3D modeling of proteins would have looked to Pagadala to determine which program best meets the requirement to calculate a degree of fit of a candidate ligand to a 3D representation of a protein. Such a combination is merely a "predictable use of prior art elements according to their established functions." KSR Int’l 7, 127 S. Ct. at 1740.
With respect to claim 7, Singal provides Rel conformations bound to (p)ppGpp, and atomic coordinates meeting the BRI of those of Table 3, and subsets thereof. Pagadala provides programs which can model, compare and score different conformational poses of a protein, with and without the ligand.
With respect to claim 10, Singal provides how stabilization was assessed for both hydrolase and synthetase activity.
With respect to claim 12, Singal further provides in vitro assays for assessing ppGpp synthesis and hydrolysis by purified Rel proteins.
With respect to claim 13, Pagadala provides the computer-based modeling, using computers meeting the requirements. The programs identified by Pagadala can perform the generation of the 3D structure based on x-ray coordinates, fit candidate ligands to the modeled protein, and score/ select a candidate for “favorable energetic interactions.”
With respect to claims 14-15, Pagadala provides both superimposition/ rigid body modeling and flexible docking programs.
With respect to claim 16, Singal provides some amino acid residues important for enzymatic activity, which would have been important in the 3D modeling of the candidate: protein interaction.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Pausch et al. (Sept 15, 2020) Structural Basis for Regulation of the Opposing (p)ppGpp Synthetase and Hydrolase within the Stringent Response Orchestrator Rel. Cell Reports, 32: 108157, 30 pages. Pausch provides crystal structures for B. subtilis Rel protein, and Cryo-EM structures. This was published after the effective filing date of the application.
Sinha et al. (2021) The RelA hydrolase domain acts as a molecular switch for (p)ppGpp synthesis. Communications Biology, 4:434, 10 pages.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARY K ZEMAN whose telephone number is 5712720723. The examiner can normally be reached on 8am-2pm M-F. Email may be sent to mary.zeman@uspto.gov if the appropriate permissions have been filed.
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, Larry Riggs can be reached on 571 270-3062. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MARY K ZEMAN/ Primary Examiner, Art Unit 1686
Prosecution Insights