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 .
Claim Status
Claims 14-26 are currently pending and under examination herein.
Claims 14-26 are rejected.
Claims 1 is objected to.
Priority
The instant application claims priority as a 371 of PCT/EP2020/087597 filed 22 December 2020 and EP19306751.9 filed 23 December 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. In this action, claims 14-26 are examined as though they had an effective filing date of 23 December 2019. In future actions, the effective filing date of one or more claims may change, due to amendments to the claims, or further analysis of the disclosure(s) of the priority application(s).
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 28 December 2022 and 25 March 2026 are in compliance with the provisions of 37 CFR 1.97. The Non Patent Literature (NPL) document Barbieri et al. from the IDS filed on 25 March 2026 was not found amongst the submitted NPL documents. However, a copy of this NPL was retrieved and attached as part of this office action. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings filed on 22 June 2022 are accepted.
Claim Objections
Claim 14 is objected to because of the following informalities/typographical errors:
Claim 14 recites “expression cassettes comprises least two expression cassettes” - there may be a missing “at” between “comprises” and “least”.
Claim 14 recites “as the optimal distribution the possible distribution” – there may be a missing “of” between “distribution” and “the”.
Claim 14 recites “the first subset of candidate peptides as function of” - there may be a missing “a” between “as” and “function”.
Appropriate proofreading and correction is required. Other minor errors may be present in the claims that should be addressed.
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.
Claim 22 is rejected under 35 U.S.C. 112(b) 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.
Claim 22 recites “in which class a candidate peptide shall be classified to be assigned to this slot position”. It is unclear what position “this” is referring to. Does the rule only apply with one specific position? The metes and bounds of the limitation are therefore unclear, rendering the claim indefinite. This rejection can be overcome by removing or defining “this” in regards to a slot position within the claims. For the purposes of examination “this” is interpreted to indicate any position.
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 14-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. In accordance with MPEP 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea (Step 2A, Prong 1). Claims 14-26 are directed to methods. In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 14 recites the limitation - (a) selecting a first subset of candidate peptides from a set of candidate peptides, wherein the candidate peptides of the first subset of candidate peptides present transmembrane scores below a transmembrane score threshold, wherein the transmembrane score of a candidate peptide is indicative of a probability that the candidate peptide bears at least one transmembrane segment; (c) for each of the one or more expression cassettes, determining an optimal slot assignment of the candidate peptides of the first subset of candidate peptides as function of a cassette slot occupancy rule so as to select a peptide fusion with a lowest transmembrane score, wherein said cassette slot occupancy rule defines possible slot positions of candidate peptides of the first subset of candidate peptides within an expression cassette according to transmembrane scores of the candidate peptides, and, in case of equal transmembrane scores, according to hydropathy scores of the candidate peptides; and (d) determining a DNA transfer sequence comprising a nucleotide sequence of the one or more expression cassette for generation of said recombinant poxvirus. Based on the broadest reasonable interpretation, selecting a first subset, determining an optimal slot assignment, and determining a DNA transfer sequence could practically be done by the human mind. This draws the limitations to a mental process, which classifies the limitations as an abstract idea. Claim 14 also recites b) determining an optimal distribution of the candidate peptides of the first subset of candidate peptides to one or more expression cassette among a plurality of possible distributions, wherein said determining comprises, when the one or more expression cassettes comprises least two expression cassettes, calculating for each possible distribution a range between hydropathy scores of the at least two expression cassettes and selecting as the optimal distribution the possible distribution having the lowest range. Based on the broadest reasonable interpretation, determining an optimal distribution, which includes calculating a range and selecting an optimal distribution could include equations and could practically be done by the human mind. This draws the limitation to a mathematical concept and a mental process, which classifies the limitation as an abstract idea.
Claim 15 recites the limitation - wherein the candidate peptides of the first subset of candidate peptides present continuous regions below a homology threshold. This limitation specifies the candidate peptides selected in the judicial exception of claim 14. The refined selection indicated by this limitation still represents a judicial expectation.
Claim 16 recites the limitation - wherein the plurality of possible distributions does not exceed a given maximum number of possible distributions. This limitation specifies the possible distributions determined in the judicial exception of claim 14. The refined determination indicated by this limitation still represents a judicial expectation.
Claim 17 recites the limitation - wherein the plurality of possible distributions does not exceed a given maximum number of possible distributions. This limitation specifies the possible distributions determined in the judicial exception of claim 14. The refined determination indicated by this limitation still represents a judicial expectation. Claim 17 also recites wherein step (a) comprises discarding candidate peptides which transmembrane scores is above the transmembrane score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset. Based on the broadest reasonable interpretation, discarding candidate peptides and selecting a second subset could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea.
Claim 18 reties the limitation - wherein the plurality of possible distributions does not exceed a given maximum number of possible distributions. This limitation limits the possible distributions determined in the judicial exception of claim 14. The refined determination indicated by this limitation still represents a judicial expectation. Claim 18 also recites and wherein step (a) comprises discarding candidate peptides which transmembrane scores is above the transmembrane score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset. Based on the broadest reasonable interpretation, discarding candidate peptides and selecting a second subset could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea. Claim 18 also recites when for each possible distribution, at least one expression cassette presents an hydropathy score above a given threshold, reiterating step (b) with another plurality of possible distributions. Step (b) recites at least one judicial exception which is therefore recited by this limitation (See claim 14 of the current Rejection). Claim 18 also recites replacing the candidate peptide from the first subset of candidate peptides presenting the highest hydropathy score by a candidate peptide from the second subset of candidate peptides and reiterating step (a). Step (a) recites at least one judicial exception which is therefore recited by this limitation (See claim 14 of the current Rejection).
Claim 19 recites the limitation - wherein step (c) further comprises discarding any peptide fusion that displays at least one transmembrane patch with a score above a transmembrane patch score threshold. Based on the broadest reasonable interpretation, discarding a peptide based on a score could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea.
Claim 20 recites the limitation - wherein step (c) further comprises discarding any peptide fusion that displays at least one transmembrane patch with a score above a transmembrane patch score threshold. Based on the broadest reasonable interpretation, discarding a peptide based on a score could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea. Claim 20 also recites wherein step (a) comprises discarding candidate peptides which transmembrane scores is above the transmembrane score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset. Based on the broadest reasonable interpretation, discarding a candidate peptide based on a score and selecting a second set could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea.
Claim 21 recites the limitation - wherein step (c) further comprises discarding any peptide fusion that displays at least one transmembrane patch with a score above a transmembrane patch score threshold. Based on the broadest reasonable interpretation, discarding a peptide based on a score could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea. Claim 21 also recites wherein step (a) comprises discarding candidate peptides which transmembrane scores is above the transmembrane score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset. Based on the broadest reasonable interpretation, discarding a candidate peptide based on a score and selecting a second set could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea. Claim 21 also recites wherein step (c) comprises, when at least one transmembrane domain is detected in any possible slot assignment of the candidate peptides in an expression cassette, replacing the candidate peptide from the first subset of candidate peptides presenting the highest transmembrane score by a candidate peptide from the second subset. Based on the broadest reasonable interpretation, replacing a peptide based on a score could practically be done by the human mind. This draws the limitation to a mental process, which classifies the limitation as an abstract idea. Claim 21 also recites repeating steps (b) then (c). Steps (b) and (c) recite at least one judicial exception which is therefore recited by this limitation (See claim 14 of the current Rejection).
Claim 22 recites the limitation - wherein the candidates peptides distributed to an expression cassette are classified in one of at least three classes. This limitation limits the candidate peptides distributed in the judicial exception of claim 14. The refined determination indicated by this limitation still represents a judicial expectation. Claim 22 also recites wherein said cassette slot occupancy rule defines, for each slot position of an expression cassette, in which class a candidate peptide shall be classified to be assigned to this slot position. This limitation refines the determining rule in the judicial exception of claim 14. The refined determination indicated by this limitation still represents a judicial expectation.
Claim 23 recites the limitation - wherein there is/are a single expression cassette when the number of candidate peptides in the first subset of candidate peptides is below 10, two expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 10 and 14, and three expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 15 and 30. This limitation refines the number of cassettes when determining the distribution recited in the judicial exception of claim 14. The refined determination indicated by this limitation still represents a judicial expectation.
Claim 24 recites the limitation - performing the method of claim 14 for designing said recombinant poxvirus. The method of claim 14 recites at least one judicial exception which is therefore recited by this limitation (See claim 14 of the current Rejection).
Claim 26 recites the limitation - wherein there is/are a single expression cassette when the number of candidate peptides in the first subset of candidate peptides is below 10, two expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 10 and 14, and three expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 15 and 30. This limitation limits the number of cassettes when determining the distribution recited in the judicial exception of claim 14. The refined determination indicated by this limitation still represents a judicial expectation. Claim 26 also recites wherein said recombinant poxvirus encodes neopeptides. This limitation limits the DNA transfer sequence determining recited in the judicial exception of claim 14. The refined determination indicated by this limitation still represents a judicial expectation.
These limitations recite concepts of selecting, determining, and calculating information that are so generically recited that they can be practically performed in the human mind as claimed, which falls under the “Mental processes” and “Mathematical concepts” grouping of abstract ideas. These recitations are similar to the concepts of collecting information, analyzing it and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)) and comparing information regarding a sample or test to a control or target data in Univ. of Utah Research Found. v. Ambry Genetics Corp. (774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014)) and Association for Molecular Pathology v. USPTO (689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)) that the courts have identified as concepts that can be practically performed in the human mind or mathematical relationships. Therefore, these limitations fall under the “Mental process” and “Mathematical concepts” groupings of abstract ideas. As such, claims 14-26 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). These judicial exceptions are not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology (MPEP § 2106.04(d)(1)). Rather, the claims provide insignificant extra-solution activity (MPEP § 2106.05(g)) and provide mere instructions to apply a judicial exception (MPEP § 2106.05(f)). Specifically, the claims recite the following additional elements:
Claim 14 recites performing by processing means of a server
Claim 24 recites generating said recombinant poxvirus.
Claim 25 recites wherein said process further comprises a manufacturing step of said recombinant poxvirus, wherein said manufacturing step comprises amplifying the recombinant poxvirus in a producer cell and recovering the amplified recombinant poxvirus.
There is no indication that these steps are affected by the judicial exception in any way and thus do not integrate the recited judicial exception into a practical application. As such, claims 14-26 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite conventional additional elements that equate to mere instructions to apply the recited exception in a generic way or in a generic computing environment. The claims also recite conventional additional elements that represent insignificant extra-solution activities.
As discussed above, there are no additional limitations to indicate that the claimed selecting, determining, and calculating information require anything other than generic computer components in order to carry out the recited abstract idea in the claims. Claims that amount to nothing more than an instruction to apply the abstract idea using a generic computer do not render an abstract idea eligible. Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. MPEP 2106.05(f) discloses that mere instructions to apply the judicial exception cannot provide an inventive concept to the claims. As specified in MPEP 2106.05(g), extra-solution activities can be understood as incidental to the primary process or product that are merely a nominal or tangential addition to the claim. Additionally, Cheltsov et al. (2010, Journal of Medicinal Chemistry, Vol. 53: 3899-3906), Kremer et al. (2012, Vaccinia Virus and Poxvirology: Methods and Protocols, Methods in Molecular Biology, Chapter 4: 59-92), and Song et al. (2013, Journal of Virology, Vol. 87, No. 21: 11950- 11954) demonstrate the additional elements individually and in combination are well understood, routine, and conventional. Specifically, all demonstrate methods for recombinant pox virus production including amplification (Cheltsov et al., Page 3509, Column 1, Paragraph 2: the recombinant virus expressing green fluorescent protein (GFP) fused to the influenza virus nucleoprotein were grown; Kremer et al., Page 60, Paragraph 2: the engineered MVA must be thoroughly controlled for genetic stability and fitness for large-scale amplification (e.g., for vaccine production); Song et al., Page 11950, Column 2, Paragraph 2: MVA expressing MERS-S or MERS-SHA was obtained using standard methods to generate recombinant MVA vaccines suitable for clinical testing) and recovery (Cheltsov et al., Page 3509, Column 1, Paragraph 2: The virus titer was measured; Kremer et al., Page 60, Paragraph 2: The protocols include well-established techniques for isolation of cloned viruses; Song et al., Page 11950, Column 2, Paragraph 2: isolate clonal recombinant viruses by screening for fluorescent cell foci during repetitive plaque purification) involving server based methods (Cheltsov et al., Page 3905, Column 2, Paragraph 2: resulting structures were submitted to DCOMPLEX server; Kremer et al., Page 68, Paragraph 1: using spot counting software; Song et al., Page 11951, Column 1, Paragraph 2: NetNGlyc server analysis suggested at least 17 likely Nglycosylation sites).
The additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, Claims 14-26 are not patent eligible.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 14, 19-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Petit et al. (US 20190032064 A1), in view of Appaiah et al. (US 20130273585 A1). Italicized text from reference art.
The applicable claims include:
Claim 14. A method of designing a recombinant poxvirus, comprising performing by processing means (11) of a server (1) the steps of: (a) selecting a first subset of candidate peptides from a set of candidate peptides, wherein the candidate peptides of the first subset of candidate peptides present transmembrane scores below a transmembrane score threshold, wherein the transmembrane score of a candidate peptide is indicative of a probability that the candidate peptide bears at least one transmembrane segment; (b) determining an optimal distribution of the candidate peptides of the first subset of candidate peptides to one or more expression cassette among a plurality of possible distributions, wherein said determining comprises, when the one or more expression cassettes comprises least two expression cassettes, calculating for each possible distribution a range between hydropathy scores of the at least two expression cassettes and selecting as the optimal distribution the possible distribution having the lowest range; (c) for each of the one or more expression cassettes, determining an optimal slot assignment of the candidate peptides of the first subset of candidate peptides as function of a cassette slot occupancy rule so as to select a peptide fusion with a lowest transmembrane score, wherein said cassette slot occupancy rule defines possible slot positions of candidate peptides of the first subset of candidate peptides within an expression cassette according to transmembrane scores of the candidate peptides, and, in case of equal transmembrane scores, according to hydropathy scores of the candidate peptides; (d) determining a DNA transfer sequence comprising a nucleotide sequence of the one or more expression cassette for generation of said recombinant poxvirus.
Claim 19. The method of claim 14, wherein step (c) further comprises discarding any peptide fusion that displays at least one transmembrane patch with a score above a transmembrane patch score threshold.
Claim 20. The method of claim 14, i. wherein step (c) further comprises discarding any peptide fusion that displays at least one transmembrane patch with a score above a transmembrane patch score threshold and ii. wherein step (a) comprises discarding candidate peptides which transmembrane scores is above the transmembrane score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and iii. selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset.
Claim 21. The method of claim 14, i. wherein step (c) further comprises discarding any peptide fusion that displays at least one transmembrane patch with a score above a transmembrane patch score threshold, ii. wherein step (a) comprises discarding candidate peptides which transmembrane scores is above the transmembrane score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset, and iii. wherein step (c) comprises, when at least one transmembrane domain is detected in any possible slot assignment of the candidate peptides in an expression cassette, replacing the candidate peptide from the first subset of candidate peptides presenting the highest transmembrane score by a candidate peptide from the second subset, and repeating steps (b) then (c).
Claim 22. The method of claim 14, i. wherein the candidates peptides distributed to an expression cassette are classified in one of at least three classes and ii. wherein said cassette slot occupancy rule defines, for each slot position of an expression cassette, in which class a candidate peptide shall be classified to be assigned to this slot position.
Claim 23. The method of claim 14, wherein there is/are a single expression cassette when the number of candidate peptides in the first subset of candidate peptides is below 10, two expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 10 and 14, and three expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 15 and 30.
Claim 26. The method according to claim 14, i. wherein there is/are a single expression cassette when the number of candidate peptides in the first subset of candidate peptides is below 10, two expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 10 and 14, and three expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 15 and 30, and ii. wherein said recombinant poxvirus encodes neopeptides.
Regarding Claim 14, Petit et al. teach (Claim 1.a) selecting a first subset of candidate peptides from a set of candidate peptides (Page 39, Paragraph 0426: nonsensical peptide or frameshift-mutation-derived peptide sequences can be selected. The selected peptides can then be arranged into one or more candidate orders for a potential recombinant polypeptide; Page 39, Paragraph 0428: a process as described herein, additionally comprises the step of selecting one or more neo-epitopes, nonsensical peptides or recombinant polypeptide comprising one or more neo-epitopes that are hydrophilic). The selection is based on physiochemical properties related to, but not explicitly based on, transmembrane potential, although it would be obvious to use (see reason to combine and Appaiah et al. teachings below). Petit et al. teach also teach (Claim 1.b) determining an optimal distribution of the first subset of candidate peptides to one or more expression cassette, wherein said determining comprises, when the one or more expression cassettes comprises least two expression cassettes, calculating for each possible distribution a range between hydropathy scores and selecting the possible distribution having the lowest range (Page 38, Paragraph 0417: The one or more different peptide sequences can be further characterized. For example, the one or more different peptide sequences and excluding a peptide sequence if it does not score below a hydropathy threshold; Page 39, Paragraph 0426: The selected peptides can then be arranged into one or more candidate orders for a potential recombinant polypeptide. If there are more usable peptides than can fit into a single plasmid, different peptides can be assigned priority ranks as needed/desired and/or split up into different recombinant polypeptides. Priority rank can be determined by factors such as relative size, priority of transcription, and/or overall hydrophobicity of the translated polypeptide). An expression cassette is interpreted as any group of peptide sequences to be transferred to a vector. The limitation after “when the one or more expression cassettes comprises least two expression cassettes” is interpreted as a contingent limitation which indicates the broadest reasonable interpretation of a method claim include only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met (MPEP 2111.04). Petit et al. also teach (Claim 14.c) for each of the expression cassettes, determining an optimal slot assignment of the candidate peptides of the first subset of candidate peptides as function of a cassette slot occupancy rule so as to select a peptide fusion, wherein said cassette slot occupancy rule defines possible slot positions of candidate peptides of the first subset of candidate peptides within an expression cassette, and, in case of equal transmembrane scores, according to hydropathy scores of the candidate peptides (Page 29, Paragraph 0426: The selected peptides can then be arranged into one or more candidate orders for a potential recombinant polypeptide. If there are more usable peptides than can fit into a single plasmid, different peptides can be assigned priority ranks as needed/desired and/or split up into different recombinant polypeptides. Priority rank can be determined by factors such as relative size, priority of transcription, and/or overall hydrophobicity of the translated polypeptide; Page 41, Paragraph 0439: use of a one or more neo-epitope sequence comprised in a peptide, a recombinant polypeptide, or a fusion polypeptide provides a targeting immunotherapy). Petit et al. teach the optimal (i.e. selected) order is based on multiple parameters including hydropathy but does not teach a transmembrane score. However, it would be obvious to add the transmembrane score taught by Appaiah et al. (see Regarding Claim 1.a and reason to combine below). The limitation after “in case of equal transmembrane scores” is interpreted as a contingent limitation which indicates the broadest reasonable interpretation of a method claim include only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met (MPEP 2111.04). Petit et al. also teach (Claim 1.d) determining a DNA transfer sequence comprising a nucleotide sequence of the one or more expression cassette for generation of said recombinant poxvirus (Page 38, Paragraph 0422: screening for and selecting a nucleic acid construct encoding one or more peptides comprising one or more immunogenic neo-epitope identified; and transforming a second attenuated recombinant Listeria strain with a vector comprising a nucleic acid sequence encoding one or more peptides comprising the one or more immunogenic neo-epitopes). Additionally, Petit et al. teach the methods are applied to designing a recombinant poxvirus (Page 2, Paragraph 0013: generating an immunotherapy delivery vector comprising a nucleic acid comprising an open reading frame encoding a recombinant polypeptide comprising the one or more peptides comprising the one or more immunogenic neo-epitopes identified; Page 34, Paragraph 0382: a virus delivery vector may be selected from the following: a pox virus).
Regarding Claim 19, Petit et al. teach wherein step (c) further comprises discarding any peptide fusion that displays a patch with a score above a threshold (Page 40, Paragraph 0431: neo-epitopes scoring above a specific cutoff (around 1.6) are excluded). Petit et al. teach selecting based on scores associated with hydropathy (see Regarding Claim 14.c). Appaiah et al. teach the implementation of a transmembrane score that could be added to step c (see Regarding 14.b, Regarding Claim 14.c, and reason to combine below).
Regarding Claim 20, Petit et al. teach (Claim 20.i) wherein step (c) further comprises discarding any peptide fusion that displays a patch with a score above a threshold (see Regarding Claim 19 – identical limitations). Petit et al. also teach (Claim 20.ii) wherein step (a) comprises discarding candidate peptides which scores above the score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential (Page 40, Paragraph 0431: neo-epitopes scoring above a specific cutoff (around 1.6) are excluded). Petit et al. teach excluding based physiochemical factors such as hydrophobia but not explicitly use a transmembrane score. It would be obvious to use the transmembrane score of Appaiah et al. (See Regarding Claim 14 and reason to combine). The and/or was interpreted to mean the identity requirement was not required. Petit et al. also teach (Claim 20.iii) selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset (Page 47, Paragraph 0519: a first set can be different from a second set of neo-epitopes by virtue of not including any of the same neo-epitopes).
Regarding Claim 21, Petit et al. teach (Claim 21.i) wherein step (c) further comprises discarding any peptide fusion that displays at least one patch with a score above a patch score threshold (see Regarding Claim 19 – identical limitations). Petit et al. also teach (Claim 21.ii) wherein step (a) comprises discarding candidate peptides which scores is above the score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset (see Regarding Claim 20.ii and 20.iii – identical limitations). Petit et al. also teach (Claim 21.iii) wherein step (c) comprises, when at least one transmembrane domain is detected in any possible slot assignment of the candidate peptides in an expression cassette, replacing the candidate peptide from the first subset of candidate peptides presenting the highest score by a candidate peptide from the second subset, and repeating steps (b) then (c). (Page 38, Paragraph 0421: the process can be repeated to create a plurality of immunotherapy delivery vectors, each comprising a different set of one or more immunogenic neo-epitopes; Page 39, Paragraph 0429: selecting one or more neo-epitopes, peptide comprising one or more neo-epitopes, nonsensical peptides, or recombinant polypeptide comprising one or more neo-epitopes, that have a score of up to 1.6 in the Kyte Doolittle hydropathy plot; Page 40, paragraph 0431: If any region scores above a cutoff (e.g., around 1.6), the peptides can be reordered or shuffled within the recombinant polypeptide using selected parameters or using randomization until an acceptable order of antigenic peptides is found (i.e., one in which no region scores above the cutoff)). Appaiah et al. taught the implementation of a transmembrane score that could be used instead of hydropathy (see Regarding 14.b, Regarding Claim 14.c, and reason to combine). Additionally, the limitation following “when at least one transmembrane domain is detected in any possible slot assignment of the candidate peptides in an expression cassette” is interpreted as a contingent limitation which indicates the broadest reasonable interpretation of a method claim include only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met (MPEP 2111.04).
Regarding Claim 22, Petit et al. (Claim 22.i) wherein the candidates peptides distributed to an expression cassette are classified in one of at least three classes (Page 40, Paragraph 0437: binding prediction criteria in the field of HLA peptide binding prediction may be defined as: peptides with IC50<150 nM as strong binders, IC50 of 150 to 500 nM as intermediate to weak binders, and IC50>500 nM as nonbinders). Petit et al. (Claim 22.ii) wherein said cassette slot occupancy rule defines, for each slot position of an expression cassette, in which class a candidate peptide shall be classified to be assigned to this slot position (Page 39, Paragraph 0426: The selected peptides can then be arranged into one or more candidate orders for a potential recombinant polypeptide. If there are more usable peptides than can fit into a single plasmid, different peptides can be assigned priority ranks as needed/desired and/or split up into different recombinant polypeptides. Priority rank can be determined by factors such as relative size, priority of transcription, and/or overall hydrophobicity of the translated polypeptide).
Regarding Claim 23, Petit et al. teach there is/are a single expression cassette when the number of candidate peptides in the first subset is below 10, two expression cassettes when the number of candidate peptides in the first subset is between 10 and 14, and three expression cassettes when the number of candidate peptides in the first subset is between 15 and 30 (Page 39, Paragraph 0426: ranges of linear antigenic peptides can be starting, for example, with about 50, 40, 30, 20, or 10 antigenic peptides per plasmid). This art indicates there can be about 10 peptides per expression cassette (i.e. plasmid). The art indicates the term about can be a deviance between 0.0001 and 25% (Page 18, Paragraph 0222). This indicates an expression cassette can hold 7 to 13 peptides (10 ± 25%). This covers the ranges specified by the claims based on the number of peptides divided by the number of expression cassettes.
Regarding Claim 26, Petit et al. teach (Claim 26.i) wherein there is/are a single expression cassette when the number of candidate peptides in the first subset of candidate peptides is below 10, two expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 10 and 14, and three expression cassettes when the number of candidate peptides in the first subset of candidate peptides is between 15 and 30 (see Regarding Claim 23 – identical limitation). Petit et al. teach (Claim 26.ii) wherein said recombinant poxvirus encodes neopeptides (Page 37, paragraph 0409: a process of creating a personalized immunotherapy for a subject having a disease or condition comprises identifying and selecting neo-epitopes within mutated and variant antigens (neo-antigens) that are specific to the patient's disease). Neopeptides are commensurate in scope with neo-epitopes or neo-antigens. The diseases considered include tumors (Page 2, Paragraph 0022: In a related aspect, the one or more neo-epitopes comprises a self-antigen associated with the disease or condition, wherein the self-antigen comprises a cancer or tumor-associated neo-epitope, or a cancer-specific or tumor-specific neo-epitope).
Petit et al. does not teach selecting peptides based on transmembrane scores below a threshold, wherein the transmembrane score is indicative of a probability that the candidate peptide has a transmembrane segment (Claim 1.a). Petit et al. does not teach the use of a transmembrane score in Claims 1, 19, 20 or 21.
Regarding Claim 14, Appaiah et al. teach (Claim 1.a) selecting peptides based on transmembrane scores below a threshold, wherein the transmembrane score is indicative of a probability that the candidate peptide has a transmembrane segment (Page 2, Paragraph 0010: residues which highly correlate with such insolubility include highly hydrophobic residues in a segment of about 19 to 31 amino acids with a transmembrane probability score of at least about 0.8 by TMHMM analysis; Page 7, Paragraph 0064). Additionally, Appaiah et al. the methods are server based (Page 8, Paragraph 0082: The Dense Alignnment Surface (DAS) prediction server is meant for predicting transmembrane helices in membrane proteins). The proposed transmembrane score used for selecting against transmembrane peptides can therefore be applied when utilizing scores to selected for or against peptides in the other claims.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify Petit et al. with Appaiah et al. because Appaiah et al. teach methods for using a transmembrane score for evaluating recombinant proteins that are related to and taught to be used in conjunction with hydropathy information, which is a major focus of Petit et al (Page 7, Paragraph 0064: the prediction of transmembrane segments can also indicate likelihood of sufficient hydrophobicity to interact with other hydrophobic segments; Page 8, Paragraph 0082: This means that the transmembrane region will detect a fragment that is predominantly composed of hydrophobic amino acids, flanked by residues that are hydrophilic or polar residues; Page 9, Paragraph 0086: This method implicitly combines the hydrophobic signal to detect transmembrane (TM) segments and the charge bias, an abundance of positively charged residues in the part of the sequence on the cytoplasmic side of the membrane protein into one integrated algorithm; Page 9, Paragraph 0088: hydropathy plot can indicate potential transmembrane or surface regions in proteins). Therefore, it would have been obvious to someone of ordinary skill in the art at the time of the effective filing date to combine the methods from the references indicated above. Furthermore, one of ordinary skill in the art would predict that the methods taught by Appaiah et al. could be readily added to the method of Petit et al. with a reasonable expectation of success because Petit et al. considers multiple physiochemical measurements including hydropathy for considering recombinant proteins and considering a transmembrane score is functionally the same way as the already implemented physiochemical measurements considered by Petit et al. Accordingly, Claims 14, 19-23, and 26 taken as a whole would have been prima facie obvious before the effective filing date and are rejected under 35 U.S.C. 103.
Claims 14-15, 19-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Petit et al., as applied above to Claims 14, 19-23, and 26, in view of Appaiah et al., as applied above to claims 14, 19-23, and 26, and in further view of Negahdaripour et al. (2017, Infection, Genetics and Evolution, Vol 54: 402–416). Italicized text from reference art.
The applicable claims include:
Claims 14, 19-23, and 26 are above.
Claim 15. The method of claim 14, wherein the candidate peptides of the first subset of candidate peptides present continuous regions below a homology threshold.
Regarding claims 14, 19-23, and 26, these are taught by Petit et al. and Appaiah et al. as indicated above.
Petit et al. and Appaiah et al. do not teach the use of a homology threshold (Claim 15).
Regarding Claim 15, Negahdaripour et al. teach wherein the candidate peptides of the first subset present continuous regions below a homology threshold (Page 406, Column 2, Paragraph 8: 3.4.1. Homology modeling - The 3D structure modeling of the protein construct was performed the I-Tasser server. This server introduced 5 models, from which the best model with the highest C-score value (0.08) was selected C-score is usually in the range of [−5, 2], and a higher C-score is suggestive of a model with a higher confidence). The homology score of 0.08 was below the threshold value of 2 which was set as the upper limit.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify Petit et al. and Appaiah et al. with Negahdaripour et al. because Negahdaripour et al. teach methods of peptide vaccine optimization focusing on evaluating the physiochemical properties that are useful and efficient (Page 414, Column 2, Paragraph 1: This systematic approach is useful for development of rational vaccines while saving time and resources. The designed vaccine is expected to promote immune system effectively due to presence of several adjuvants, besides possessing acceptable physicochemical characteristics). This was a major focus of Petit et al. Therefore, it would have been obvious to someone of ordinary skill in the art at the time of the effective filing date to combine the methods from the references indicated above. Furthermore, one of ordinary skill in the art would predict that the methods taught by Negahdaripour et al. could be readily added to the methods of Petit et al. and Appaiah et al. with a reasonable expectation of success because Negahdaripour et al. is in the technical field as Petit et al. – designing and optimizing sequences of peptides within vectors directed to vaccines. Additionally, Petit et al. considers multiple physiochemical measurements of proteins related to vaccine development and considering an additional homology score is functioning in the same way as the already implemented physiochemical measurements. Accordingly, Claims 14-15, 19-23, and 26 taken as a whole would have been prima facie obvious before the effective filing date and are rejected under 35 U.S.C. 103.
Claims 14, 16-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Petit et al., as applied above to Claims 14, 19-23, and 26, in view of Appaiah et al., as applied above to claims 14, 19-23, and 26, and in further view of Schubert and Kohlbacher (2016, Genome Medicine, Vol. 8, No. 9: 1-10, IDS filed 25 March 2026). Italicized text from reference art.
The applicable claims include:
Claims 14, 19-23, and 26 are above.
Claim 16. The method of claim 14, wherein the plurality of possible distributions does not exceed a given maximum number of possible distributions.
Claim 17. The method of claim 14, i. wherein the plurality of possible distributions does not exceed a given maximum number of possible distributions and ii. wherein step (a) comprises discarding candidate peptides which transmembrane scores is above the transmembrane score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and iii. selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset.
Claim 18. The method of claim 14, i. wherein the plurality of possible distributions does not exceed a given maximum number of possible distributions and ii. wherein step (a) comprises discarding candidate peptides which transmembrane scores is above the transmembrane score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential, and iii. selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset, iv. further comprising, when for each possible distribution, at least one expression cassette presents an hydropathy score above a given threshold, reiterating step (b) with another plurality of possible distributions or replacing the candidate peptide from the first subset of candidate peptides presenting the highest hydropathy score by a candidate peptide from the second subset of candidate peptides and reiterating step (a).
Regarding claims 14, 19-23, and 26, these are taught by Petit et al. and Appaiah et al. as indicated above.
Regarding Claim 17, Petit et al. also teach (Claim 17.ii) wherein step (a) comprises discarding candidate peptides which scores is above the score threshold (Page 40, Paragraph 0431: neo-epitopes scoring above a specific cutoff (around 1.6) are excluded). Petit et al. teach excluding based physiochemical factors such as hydrophobia but not explicitly use a transmembrane score. It would be obvious to use the transmembrane score of Appaiah et al. (See Regarding Claim 14 and reason to combine). The and/or was interpreted to mean the identity requirement was not required. Petit et al. also teach (Claim 17.iii) selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset (Page 47, Paragraph 0519: a first set can be different from a second set of neo-epitopes by virtue of not including any of the same neo-epitopes).
Regarding Claim 18, Petit et al. teach (Claim 18.ii) wherein step (a) comprises discarding candidate peptides which scores is above the score threshold and/or which have a region of sequence identity above an identity threshold with another candidate peptide predicted to have a higher immunogenic potential (see Regarding Claim 17.ii – identical limitations). Petit et al. also teach (Claim 18.iii) selecting a second subset of candidate peptides wherein the candidate peptides of the second subset are neither discarded nor selected in the first subset (see Regarding Claim 17.iii – identical limitations). Petit et al. also teach (Claim 18.iv) when for each possible distribution, at least one expression cassette presents an hydropathy score above a given threshold, reiterating step (b) with another plurality of possible distributions or replacing the candidate peptide from the first subset of candidate peptides presenting the highest hydropathy score by a candidate peptide from the second subset of candidate peptides and reiterating step (a). (Page 38, Paragraph 0421: the process can be repeated to create a plurality of immunotherapy delivery vectors, each comprising a different set of one or more immunogenic neo-epitopes; Page 39, Paragraph 0429: selecting one or more neo-epitopes, peptide comprising one or more neo-epitopes, nonsensical peptides, or recombinant polypeptide comprising one or more neo-epitopes, that have a score of up to 1.6 in the Kyte Doolittle hydropathy plot). This shows certain steps of the methods can be triggered by different selections of peptides including differences generated by considering a hydropathy score. Additionally, The limitation following “when for each possible distribution, at least one expression cassette presents an hydropathy score above a given threshold” is interpreted as a contingent limitation which indicates the broadest reasonable interpretation of a method claim include only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met (MPEP 2111.04).
Petit et al. and Appaiah et al. do not teach the possible distributions does not exceed a maximum number of possible distributions (Claim 16 and 17.i and 18.i).
Regarding Claim 16, Schubert and Kohlbacher teach the possible distributions does not exceed a maximum number of possible distributions (Page 2, Figure 1: In total, there are n! possibilities to arrange n epitopes).
Regarding Claim 17, Schubert and Kohlbacher teach (Claim 17.i) wherein the plurality of possible distributions does not exceed a given maximum number of possible distributions (see Regarding Claim 16 – identical limitations).
Regarding Claim 18, Schubert and Kohlbacher teach (Claim 18.i) wherein the plurality of possible distributions does not exceed a given maximum number of possible distributions (see Regarding Claim 16 – identical limitations).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify Petit et al. and Appaiah et al. with Schubert and Kohlbacher because Schubert and Kohlbacher teach novel and demonstrated methods for optimizing peptide sequences for to vaccines (Page 9, Column 1, Paragraph 3: our method is a first framework that optimally designs both epitope order and spacers for string-of-beads vaccine (SBV) design. The mathematical method employs state of-the-art prediction methods, but does not depend on specific methods. Our model predicts an increased recovery of desired epitopes and a reduced production of neo-epitopes compared to both fixed spacer and spacer-less designs). This the major focus of Petit et al. Therefore, it would have been obvious to someone of ordinary skill in the art at the time of the effective filing date to combine the methods from the references indicated above. Furthermore, one of ordinary skill in the art would predict that the methods taught by Schubert and Kohlbacher could be readily added to the methods of Petit et al. and Appaiah et al. with a reasonable expectation of success because Schubert and Kohlbacher is in the technical field as Petit et al. – designing and optimizing sequences of peptides within vectors directed to vaccines. Accordingly, Claims 14, 16-23, and 26 taken as a whole would have been prima facie obvious before the effective filing date and are rejected under 35 U.S.C. 103.
Claims 14 and 19-26 are rejected under 35 U.S.C. 103 as being unpatentable over Petit et al., as applied above to Claims 14, 19-23, and 26, in view of Appaiah et al., as applied above to claims 14, 19-23, and 26, and in further view of Bissa et al. (2015, Journal of Translational Medicine, Vol 13., No. 80: 1-12). Italicized text from reference art.
The applicable claims include:
Claims 14, 19-23, and 26 are above.
Claim 24. A method for preparing a therapeutic vaccine comprising a recombinant poxvirus, comprising: i. performing the method of claim 14 for designing said recombinant poxvirus; ii. generating said recombinant poxvirus.
Claim 25. The method according to claim 24, wherein said process further comprises a manufacturing step of said recombinant poxvirus, wherein said manufacturing step comprises amplifying the recombinant poxvirus in a producer cell and recovering the amplified recombinant poxvirus.
Regarding claims 14, 19-23, and 26, these are taught by Petit et al. and Appaiah et al. as indicated above.
Regarding Claim 24, Petit et al. and Appaiah et al. teach (Claim 24.i) performing the method of claim 14 for designing said recombinant poxvirus (See Regarding Claim 14 above).
Petit et al. and Appaiah et al. do not teach generating a recombinant poxvirus (Claim 24.ii). Petit et al. and Appaiah et al. also do not teach a manufacturing step of said recombinant poxvirus, wherein said manufacturing step comprises amplifying the recombinant poxvirus in a producer cell and recovering the amplified recombinant poxvirus (Claim 25).
Regarding Claim 24, Bissa et al. teach (Claim 24.ii) generating said recombinant poxvirus (Page 3, Column 2, Paragraph 1: The FPE6F47R recombinant virus was amplified in CEFs, purified on a discontinuous sucrose gradient, titered, and used for mice immunization). The virus is a pox virus (Page 3, Column 1, Paragraph 4: The recombinant Fowlpox (FP) virus expressing the E6F47R protein (FPE6F47R) was obtained by in-vitro homologous recombination).
Regarding Claim 25, Bissa et al. teach a manufacturing step of said recombinant poxvirus, wherein said manufacturing step comprises amplifying the recombinant poxvirus in a producer cell and recovering the amplified recombinant poxvirus (Page 3, Column 2, Paragraph 1: The FPE6F47R recombinant virus was amplified in CEFs, purified on a discontinuous sucrose gradient, titered, and used for mice immunization). The steps of purifying and titering are interpreted to be synonymous with recovering. The virus is a pox virus (Page 3, Column 1, Paragraph 4: The recombinant Fowlpox (FP) virus expressing the E6F47R protein (FPE6F47R) was obtained by in-vitro homologous recombination).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify Petit et al. and Appaiah et al. with Bissa et al. because Bissa et al. teach novel and efficacious methods for developing a recombinant pox virus based vaccine (Page 8, Column 2, Paragraph 2: In the present study, we have described the construction of new genetic and Fowlpox (FP) recombinants that express the mutated non-oncogenic HPV-16 E6F47R protein to be used in combination as a preventive/therapeutic antitumor vaccine; Page 8, Column 2, Paragraph 3: Our results demonstrated that: (i) the pDNAE6F47R as well as FPE6F47R recombinants can correctly express the E6F47R protein in different cell lines). Additionally, Petit et al. teach their methods are intended for use with a pox virus (See regarding Claim 1). Therefore, it would have been obvious to someone of ordinary skill in the art at the time of the effective filing date to combine the methods from the references indicated above. Furthermore, one of ordinary skill in the art would predict that the methods taught by Bissa et al. could be readily added to the methods of Petit et al. and Appaiah et al. with a reasonable expectation of success because Bissa et al. teach their recombinant viruses are engineered through the use of plasmids which is also utilized by Petit et al. for generating their recombinant vectors. Accordingly, Claims 14 and 19-26 taken as a whole would have been prima facie obvious before the effective filing date and are rejected under 35 U.S.C. 103.
Double Patenting
No double patenting was identified.
Conclusion
No Claims are allowed.
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/B.H.E./Examiner, Art Unit 1687
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687
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