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 .
Detail Action
Claims 16-47 submitted on 12/4/2023 are pending for examination.
Applicants’ election on 6/16/2026 without traverse of group II (claims 1-7) directed to method of increasing the yield of a protein of interest (POI) produced by a recombinant host cell, by producing a recombinant host cell according to the method of claim 16, and expressing said GOI under the control of said ECP, Poi as antigen- binding protein, host cell as P. pastoris, FLO8 protein comprising SEQ ID NO: 1 as species selection in their response against the restriction requirement of 4/27/2026 is acknowledged. Since applicants did not argue against the restriction requirement of 4/27/2026 the election against the restriction requirement of 4/27/2026. Applicants request of resignment is noted; however Claim 16- 31 belong to different method which is method of making host cell which is different from the method of making product of claims 32-47 ( group II, elected group) using host cell made by the method of claims 16-31. Claims 16-31 comprise non elected subject matter therefore are withdrawn. Claims 32-47 are for examination.
Election made final.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/24/2023 in compliance with the provisions of 37 CFR 1.97. Accordingly, the examiner has considered the IDS statement.
Claim Rejections: 35 USC § 112(b)
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 32, 33-34 and 43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 32 as presented is rejected being indefinite for depending on withdrawn claim 16. Claim 32 should be independent claim. Correction is required
For examination purpose Claim 32 is written as independent claim 32 by incorporation host cell of claim 16 and as written as follows:
Claim 32. A method of increasing the yield of a protein of interest (POI) produced by a recombinant host cell wherein expression of an endogenous FLO8 protein is reduced compared to an endogenous expression of said FLO8 protein in a corresponding wild-type host cell, which host cell comprises a heterologous expression cassette comprising a gene of interest (GOI) under control of an expression cassette promoter (ECP) which ECP is not methanol-controlled and repressible by a carbon source that is not methanol, comprising engineering a host cell for reducing said endogenous FLO8 protein expression; and to incorporate said heterologous expression cassette
and expressing said GOI under the control of said ECP.
Claim 33 is rejected as being indefinite in reciting “growth-limiting amount” make the claims unclear as it fails what is growth limiting amount and it is a relative term..
Claim 34 is rejected as being indefinite in reciting “the AOX1 promoter” make the claims unclear because the AOX1 promoter lack antecedent basis because AOX1 promoter is not recited prior in the claim nor tin the claims from which claim 34 dependents.
Claim 43 is rejected as being indefinite in reciting “such as Pichia pastoris, Komagataella phaffii, Komagataella pastoris, Komagataella pseudopastoris, Saccharomyces cerevisiae, Ogataea minuta, Kluyveromces lactis, Kluyveromes marxianus, Yarrowia lipolytica or Hansenula polymorpha; or b) a cell of filamentous fungi, such as Aspergillus awamori or Trichoderma reesei” make the claims unclear because it is unclear what else other species of unknown types be there besides the recited species after such as.
Claim Rejections, 35 U.S.C 112(a) 1st Paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 32-45, 47 are rejected under 35 U.S.C. 112(a), first paragraph, as containing subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
It is noted that MPEP 2111.01 states that "[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow." In this case, in light of the specification, the examiner has broadly interpreted the claims reciting a recombinant host cell comprising an endogenous gene encoding a FLO8 protein comprising the amino acid sequence identified as SEQ ID NO:1 or a orthologue thereof, which host cell is engineered by one or more genetic modifications to reduce expression of said gene compared to the host cell prior to said one or more genetic modifications, and which host cell comprises a heterologous expression cassette comprising a gene of interest (GOD under the control of an expression cassette promoter (ECP) which ECP is repressible by a non-methanol carbon source in claim 1 to encompass any host cell which activity FLO8 protein is reduced or knock out by modifying any ortholog of SEQ ID NO: 1 having only 25% sequence identity to SEQ ID NO: 1( see the specification) having many structure having any variation within the 75% structure of SEQ ID NO: 1 . Therefore in light of the specification, claims are broadly interpreted to comprise any host cell which FLO8 activity is reduced by using any homolog of SEQ ID NO: 1 having any structure and function rendering the said host cell having specific activity of producing enhanced production of protein of interest ( POI)..
The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXIS 18221, at *23, quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these (paraphrased from Enzo Biochemical).University of Rochester v. G.D. Searle & Co. (69 USPQ2d 1886 (2004)) specifically points to the applicability of both Lilly and Enzo Biochemical to methods of using products, wherein said products lack adequate written description. While in University of Rochester v. G.D. Searle & Co. the methods were held to lack written description because not a single example of the product used in the claimed methods was described, the same analysis applies wherein the product, used in the claimed methods, must have adequate written description (see Enzo paraphrased above).
There is no structure-function correlation with regard to the members of the genus of any host cell which FLO8 activity is reduced by using any ortholog of SEQ ID NO: 1 having any structure and function rendering the said host cell having specific activity of producing enhanced production of protein of interest ( POI) recited in the claims. Therefore one of skill in the art would not recognize from the disclosure that applicants were in possession of the claimed invention.
The genus of host cell which FLO8 activity is reduced by using any ortholog of SEQ ID NO: 1 having any structure and function rendering the said host cell having specific activity of producing enhanced production of protein of interest ( POI) is an extremely large structurally and functionally variable genus. An argument can be made that any or more of the gene encoding SEQ ID NO: 1 for coding FLO8 enzyme or Of seq ID NOs: 3-9 can be used to find appropriate genes to modify the strain for the said method of enhanced POI synthesis . However, the art clearly teaches there is a practical limits to predict function of a polypeptide based structural homology:
A. Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that "Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, and page 105).
B. Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340,) also highlight the difficulties associated with "Prediction of protein function from protein sequence and structure": "To reason from sequence and structure to function is to step onto much shakier ground", closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein's role fundamentally (page 323, paragraph 1).
C. This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polypeptides do not necessarily share the same function and many functionally similar proteins will have little or no structural homology to disclosed proteins. For example, proteins having similar structure have different activities (structure does not always correlate to function); Witkowski et al., (Biochemistry 38:11643-11650, 1999) teaches that one conservative amino acid substitution transforms a beta -ketoacyl synthase into a malonyl decarboxylase and completely eliminates beta-ketoacyl synthase activity. The art also teaches that functionally similar molecules have different structures; Kisselev L., (Structure, 2002, Vol. 10: 8-9) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
As stated above, no information beyond the characterization of a few species; such as gene encoding SEQ ID NO: 1 or 3-9 for coding FLO8 has been provided by the applicants’, which would indicate that they had the possession of the claimed use of any host cell reduced expression of genus of FLO8 by modifying any ortholog of SEQ ID NO: 1 having any structure and function. The claimed genera of genus of homolog of SEQ ID NO: 1 have widely variable structures and associated functions. As it is discussed above, a minor changes in structure may result in changes affecting function, since, the specification provided no additional information (species/variant/mutant) correlating structure with function, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Furthermore, "Possession may not be shown by merely describing how to obtain possession of members of the claimed ,genus or how to identify their common structural features" (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895). A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the .gene does (function), rather what it is (structure), see University of California v. Eli Lilly & Co., 43 USPQ2d 1938, thus above claims lack adequate written description.
Applicants' are referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov
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) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
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 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.
According to MPEP 2143:"Exemplary rationales that may support a conclusion of obviousness include:(A) Combining prior art elements according to known methods to yield predictable results;(B) Simple substitution of one known element for another to obtain predictableresults;(C) Use of known technique to improve similar devices (methods, or products) in the same way;(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel."
Claims 32-45, 47 are rejected under 35 U.S.C. 103(a) as being unpatentable over Brigitte et al (WO 2015/158808 ( IDS) US PAT 10865416, US pub 20170029827) in view of D3: WO 2017/021541; D4: CORINNA REBNEGGER ET AL( APPLIED AND ENVIRONMENTAL MICROBIOLOGY, vol. 82, no. 15, 1 August 2016, pages 4570-4583, IDS); D5: ROLAND PRIELHOFER ET AL: (MICROBIAL CELL FACTORIES, vol. 12, no. 1, 1 January 2013, page 5,IDS); D6 (EP 2 669 375 A1, IDS) and D7: WO 2013/050551 , IDS) ( see Parent case 17/421619 for refences).
Brigitte et al disclose recombinant host cell, such as Pichia pastoris and a method of expressing a protein of interest (POI) from the host cell. particularly to improving a host cell's capacity to express and/or secrete a protein of interest and use of the host cell for protein expression ( abstract). Brigitte et al also disclose cell culture technology using the recombinant host cell , and more specifically to culturing said cells to produce desired molecules for medical purposes or food products ( para 001).
Brigitte et al disclose recombinant host cell, such as Pichia pastoris for improve the host cell's capacity to express and/or secrete a protein of interest (POI) by underexpress certain proteins (called KO1 protein FLO8 ( para 0212)) which are endogenous to the host cell (and which have proven to reduce the yield of protein production when overexpressed). And one of this KO protein described in D2 is FIO8 (named KO1 . Brigitte et al disclose the used Inducible (pAOX1) or constitutive (pGAP) promoters have been used. The FLO8 protein mentioned by Brigitte et al as disclose in the recombinant host cell comprise SEQ ID NO: 10 which is 100% identical to applicants SEQ ID NO: 1. See sequence alignment below:
Sequence alignment with instant application SEQ ID NO: 1.
RESULT 1
US-15-304-050-10
; Sequence 10, Application US/15304050
; Publication No. US20170029827A1
; GENERAL INFORMATION
; APPLICANT: Boehringer Ingelheim RCV GMBH & CO KG
; APPLICANT:Sandoz AG
; APPLICANT:VTU Technology GmbH
; APPLICANT:Lonza Ltd.
; TITLE OF INVENTION: RECOMBINANT HOST CELL ENGINEERED TO OVEREXPRESS HELPER PROTEINS
; FILE REFERENCE: SCHIWECK1120-1
; CURRENT APPLICATION NUMBER: US/15/304,050
; CURRENT FILING DATE: 2016-10-13
; PRIOR APPLICATION NUMBER: PCT/EP2015/058242
; PRIOR FILING DATE: 2015-04-16
; PRIOR APPLICATION NUMBER: EP14165186
; PRIOR FILING DATE: 2014-04-17
; NUMBER OF SEQ ID NOS: 163
; SOFTWARE: PatentIn version 3.5
; SEQ ID NO 10
; LENGTH: 806
; TYPE: PRT
; ORGANISM: Pichia pastoris
US-15-304-050-10
Query Match 100.0%; Score 4294; DB 16; Length 806;
Best Local Similarity 100.0%;
Matches 806; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MNKPNGSEQQPPSRGMKQESGGPVTSSTTPGTNTGLENSHSMGADMEPDVGATSPRHLLN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MNKPNGSEQQPPSRGMKQESGGPVTSSTTPGTNTGLENSHSMGADMEPDVGATSPRHLLN 60
Qy 61 GYIYDYLVKSNMQNLADQFAQETELLETDLTVPMDTPSGYLLEWWMVFWDLFNARLKQRG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GYIYDYLVKSNMQNLADQFAQETELLETDLTVPMDTPSGYLLEWWMVFWDLFNARLKQRG 120
Qy 121 SQKAHQYIQLNMLRQQQQRTMRNTARVQKVPLRPHTQSSPSMSQTFIPQQPQQQAQGQQH 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SQKAHQYIQLNMLRQQQQRTMRNTARVQKVPLRPHTQSSPSMSQTFIPQQPQQQAQGQQH 180
Qy 181 AQAQAQVQAHQQAQHHAQAQVPVQPQQHQLGGQTQQQQSINTGSPAGPNAINSRVQHLAQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AQAQAQVQAHQQAQHHAQAQVPVQPQQHQLGGQTQQQQSINTGSPAGPNAINSRVQHLAQ 240
Qy 241 QQMNHLRQQATATTQQPIPQQNIPSNQQGPTGPYPTSPSRRPRLLSNESGASAPSVMTKS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 QQMNHLRQQATATTQQPIPQQNIPSNQQGPTGPYPTSPSRRPRLLSNESGASAPSVMTKS 300
Qy 301 QLQGVPPSQQPHQQQGQQVGPPNQHQGQSSSFYSGMPPQGVVVPHQFNPQQYANMLARQQ 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QLQGVPPSQQPHQQQGQQVGPPNQHQGQSSSFYSGMPPQGVVVPHQFNPQQYANMLARQQ 360
Qy 361 HVQAQQQVQLQQVQHVQQRQQQDQQQHRLSAGSPGHPSFGVFQQPPPMSNHNQVMINQQG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 HVQAQQQVQLQQVQHVQQRQQQDQQQHRLSAGSPGHPSFGVFQQPPPMSNHNQVMINQQG 420
Qy 421 ETFFDPHSPYAQPNGYPQPQQQQQQQQQQQQQQQPQQQQQQQQQQKQQPPPPPRQPQRQQ 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 ETFFDPHSPYAQPNGYPQPQQQQQQQQQQQQQQQPQQQQQQQQQQKQQPPPPPRQPQRQQ 480
Qy 481 AMAMAPLPHSTSAAGTPHSSTTPRFSQPGPVYQQPLPASQPQHSPPSSIQQPELVPTPGS 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 AMAMAPLPHSTSAAGTPHSSTTPRFSQPGPVYQQPLPASQPQHSPPSSIQQPELVPTPGS 540
Qy 541 QHQQIAQPQSQSQHQQSQQSQSSASKIVGIQEYQKELMMLEKQNKQRHDMACKKGSGHFS 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 QHQQIAQPQSQSQHQQSQQSQSSASKIVGIQEYQKELMMLEKQNKQRHDMACKKGSGHFS 600
Qy 601 NFDPIPEHTPPEPKFNVNVMLPPQNSAVVTKNTPGTSPGTQTQNTAHSTGNTSAGSTPNN 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 NFDPIPEHTPPEPKFNVNVMLPPQNSAVVTKNTPGTSPGTQTQNTAHSTGNTSAGSTPNN 660
Qy 661 VAPVRKKKEPAKKKAKKATEPPTPTTPQTPIAARTHQNSTGGIPGNNAATKRRKREPLVD 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 VAPVRKKKEPAKKKAKKATEPPTPTTPQTPIAARTHQNSTGGIPGNNAATKRRKREPLVD 720
Qy 721 QTVSPNLNEASKSTKTGKISSQTDFTGSDNGFLQDFGDGTGPPTGTDDMEFDFNSFLNNE 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 QTVSPNLNEASKSTKTGKISSQTDFTGSDNGFLQDFGDGTGPPTGTDDMEFDFNSFLNNE 780
Qy 781 TGEPNSSTIHFDNVFNWGEGTEAGDL 806
||||||||||||||||||||||||||
Db 781 TGEPNSSTIHFDNVFNWGEGTEAGDL 806
The other features defined in the instant claims that is with the choice of ECP inducible or expression cassette regulation in the presence of growth-limiting amount of a non- methanol source (or variation of yeast cell genus) can be derived from the other prior art or routine knowledge of the skilled person in the art ( see D3: WO 2017/021541; D4: CORINNA REBNEGGER ET AL( APPLIED AND ENVIRONMENTAL MICROBIOLOGY, vol. 82, no. 15, 1 August 2016, pages 4570-4583, IDS); D5: ROLAND PRIELHOFER ET AL: (MICROBIAL CELL FACTORIES, vol. 12, no. 1, 1 January 2013, page 5,IDS); D6 (EP 2 669 375 A1, IDS) and D7: WO 2013/050551 , IDS)). Concerning the use of promoter and inducible constructs in yeast, many prior art disclose various alternatives: The authors in D4 describe glucose-limited chemostat cultures of a P. pastoris flo8 deletion mutant to prevent filter clogging. Promoters used for protein production in recombinant host cells are either regulated (e.g., induced upon addition of methanol to the medium, methanol-controlled), or constantly active (constitutive). Methanol- controlled promoters lead to technical limits, such as waste heat in the reactor or oxygen supply. In particular D4 studies showed that P. pastoris reacts to decreasing growth rates and glucose supply by the downregulation of biosynthetic processes such as gene expression and translation and the upregulation of catabolic processes and stress-responsive genes. From D4, it appears that P. pastoris reduces its maintenance energy requirement at extremely low level, a phenomenon not previously observed in eukaryotes. Transcriptional reprogramming toward zero growth included the upregulation of many transcription factors as well as stress-related genes and the downregulation of cell cycle genes. This study underlines the relevance of comparative analysis of maintenance energy metabolism, which has an important impact on large- scale industrial processes.
Especially D3 discloses variants of a carbon source, glucose regulatable promoter of P. pastoris (designated pG1, SEQ ID NO: 53 which is 100% identical to applicants ECP of SEQ ID NO: 10 see sequence alignment below ), which are regulated by a carbon source other than methanol, i.e. not methanol controlled, e.g. repressed in the presence of a carbon source such as glucose during a growth phase, and induced by limiting the carbon source in the production phase. D3 refers to an isolated artificial promoter, which is a functional variant or derivative of the carbon source regulatable pG1 promoter of Pichia pastoris .
Sequence alignment with instant application SEQ ID NO: 10
RESULT 1
BDN91562
ID BDN91562 standard; DNA; 1240 BP.
XX
AC BDN91562;
XX
DT 06-APR-2017 (first entry)
XX
DE Pichia pastoris derived DNA, SEQ ID 53.
XX
KW antibiotic; antibody production; cytokine; ds; enzyme production;
KW hormone; protein production; vaccine, general.
XX
OS Komagataella pastoris.
XX
CC PN WO2017021541-A1.
XX
CC PD 09-FEB-2017.
XX
CC PF 05-AUG-2016; 2016WO-EP068784.
XX
PR 05-AUG-2015; 2015WO-EP068024.
PR 05-APR-2016; 2016EP-00163932.
XX
CC PA (LONZ ) LONZA LTD.
XX
CC PI Mattanovich D, Gasser B, Prielhofer R;
XX
DR WPI; 2017-108147/16.
XX
CC PT New isolated or artificial pG1-x promoter useful for producing protein of
CC PT interest e.g. antibodies, , enzymes and peptides, protein antibiotics,
CC PT toxin fusion proteins, structural proteins, and regulatory proteins.
XX
CC PS Claim 14; SEQ ID NO 53; 242pp; English.
XX
CC The present invention relates to a novel isolated or artificial pG1-x
CC promoter useful for producing protein of interest (POI). The POI includes
CC heterologous protein chosen from therapeutic proteins including
CC antibodies or its fragments, enzymes and peptides, protein antibiotics,
CC toxin fusion proteins, carbohydrate-protein conjugates, structural
CC proteins, regulatory proteins, vaccines and vaccine like proteins or
CC particles, process enzymes, growth factors, hormones and cytokines and
CC metabolite of POI. The invention further relates to: (1) an expression
CC construct; (2) a recombinant host cell; and (3) method for producing POI
CC by culturing a recombinant host cell line. The present sequence
CC represents a Pichia pastoris derived DNA, which is useful for producing
CC POI.
XX
SQ Sequence 1240 BP; 325 A; 257 C; 252 G; 406 T; 0 U; 0 Other;
Query Match 100.0%; Score 1240; DB 55; Length 1240;
Best Local Similarity 100.0%;
Matches 1240; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 CAAACATTTGCTCCCCCTAGTCTCCAGGGAAATGTAAAATATACTGCTAATAGAAAACAG 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 CAAACATTTGCTCCCCCTAGTCTCCAGGGAAATGTAAAATATACTGCTAATAGAAAACAG 60
Qy 61 TAAGACGCTCAGTTGTCAGGATAATTACGTTCGACTGTAGTAAAACAGGAATCTGTATTG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TAAGACGCTCAGTTGTCAGGATAATTACGTTCGACTGTAGTAAAACAGGAATCTGTATTG 120
Qy 121 TTAGAAAGAACGAGAGTTTTTTACGGCGCCGCCATATTGGGCCGTGTGAAAACAGCTTGA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TTAGAAAGAACGAGAGTTTTTTACGGCGCCGCCATATTGGGCCGTGTGAAAACAGCTTGA 180
Qy 181 AACCCCACTACTTTCAAAGGTTCTGTTGCTATACACGAACCATGTTTAACCAACCTCGCT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 AACCCCACTACTTTCAAAGGTTCTGTTGCTATACACGAACCATGTTTAACCAACCTCGCT 240
Qy 241 TTTGACTTGACTGAAGTCATCGGTTAACAATCAAGTACCCTAGTCTGTCTGAATGCTCCT 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TTTGACTTGACTGAAGTCATCGGTTAACAATCAAGTACCCTAGTCTGTCTGAATGCTCCT 300
Qy 301 TTCCATATTCAGTAGGTGTTTCTTGCACTTTTGCATGCACTGCGGAAGAATTAGCCAATA 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 TTCCATATTCAGTAGGTGTTTCTTGCACTTTTGCATGCACTGCGGAAGAATTAGCCAATA 360
Qy 361 GCGCGTTTCATATGCGCTTTTACCCCCTCTTTTGTCAAGCGCAAAATGCCTGTAAGATTT 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 GCGCGTTTCATATGCGCTTTTACCCCCTCTTTTGTCAAGCGCAAAATGCCTGTAAGATTT 420
Qy 421 GGTGGGGGTGTGAGCCGTTAGCTGAAGTACAACAGGCTAATTCCCTGAAAAAACTGCAGC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GGTGGGGGTGTGAGCCGTTAGCTGAAGTACAACAGGCTAATTCCCTGAAAAAACTGCAGC 480
Qy 481 TCAGGGATTCCCACTATTTGGTATTCTGATATGTTTTTCCTGATATGCATCAAAACTCTA 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 TCAGGGATTCCCACTATTTGGTATTCTGATATGTTTTTCCTGATATGCATCAAAACTCTA 540
Qy 541 ATCTAAAACCTGAATCTCCGCTATTTTTTTTTTTTTTTGATGACCCCGTTTTCGTGACAA 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 ATCTAAAACCTGAATCTCCGCTATTTTTTTTTTTTTTTGATGACCCCGTTTTCGTGACAA 600
Qy 601 ATTAATTTCCAACGGGGTCTTGTCCGGATAAGAGAATTTTGTTTGATTATCCGTTCGGAT 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 ATTAATTTCCAACGGGGTCTTGTCCGGATAAGAGAATTTTGTTTGATTATCCGTTCGGAT 660
Qy 661 AAATGGACGCCTGCTCCATATTTTTCCGGTTATTACCCCACCTGGAAGTGCCCAGAATTT 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AAATGGACGCCTGCTCCATATTTTTCCGGTTATTACCCCACCTGGAAGTGCCCAGAATTT 720
Qy 721 TCCGGGGATTACGGATAATACGGTGGTCTGGATTAATTAATACGAGATCTCAGGGATTCC 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 TCCGGGGATTACGGATAATACGGTGGTCTGGATTAATTAATACGAGATCTCAGGGATTCC 780
Qy 781 CACTATTTGGTATTCTGATATGTTTTTCCTGATATGCATCAAAACTCTAATCTAAAACCT 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 CACTATTTGGTATTCTGATATGTTTTTCCTGATATGCATCAAAACTCTAATCTAAAACCT 840
Qy 841 GAATCTCCGCTATTTTTTTTTTTTTTTGATGACCCCGTTTTCGTGACAAATTAATTTCCA 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 GAATCTCCGCTATTTTTTTTTTTTTTTGATGACCCCGTTTTCGTGACAAATTAATTTCCA 900
Qy 901 ACGGGGTCTTGTCCGGATAAGAGAATTTTGTTTGATTATCCGTTCGGATAAATGGACGCC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 ACGGGGTCTTGTCCGGATAAGAGAATTTTGTTTGATTATCCGTTCGGATAAATGGACGCC 960
Qy 961 TGCTCCATATTTTTCCGGTTATTACCCCACCTGGAAGTGCCCAGAATTTTCCGGGGATTA 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 TGCTCCATATTTTTCCGGTTATTACCCCACCTGGAAGTGCCCAGAATTTTCCGGGGATTA 1020
Qy 1021 CGGATAATACGGTGGTCTGGATTAATTAATACGCCAAGTCTTACATTTTGTTGCAGTCTC 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 CGGATAATACGGTGGTCTGGATTAATTAATACGCCAAGTCTTACATTTTGTTGCAGTCTC 1080
Qy 1081 GTGCGAGTATGTGCAATAATAAACAAGATGAGCCAATTTATTGGATTAGTTGCAGCTTGA 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 GTGCGAGTATGTGCAATAATAAACAAGATGAGCCAATTTATTGGATTAGTTGCAGCTTGA 1140
Qy 1141 CCCCGCCATAGCTAGGCATAGCCAAGTGCTATGGGTGTTAGATGATGCACTTGGATGCAG 1200
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 CCCCGCCATAGCTAGGCATAGCCAAGTGCTATGGGTGTTAGATGATGCACTTGGATGCAG 1200
Qy 1201 TGAGTTTTGGAGTATAAAAGATCCTTAAAATTCCACCCTT 1240
||||||||||||||||||||||||||||||||||||||||
Db 1201 TGAGTTTTGGAGTATAAAAGATCCTTAAAATTCCACCCTT 1240
Therefore Brigitte et al (US PAT 10865416) discloses recombinant host cell to improve the host cell's capacity to express and/or secrete a protein of interest (POI) by under expressing certain proteins (called KO proteins) which are endogenous to the host cell, such as FLO8 protein ( which gene sequence of SEQ ID NO: 1 or its homolog. And which have proven to reduce the yield of protein production when overexpressed). Especially D3 discloses host cell that use non-methanol carbon source, glucose with regulatable promoter of P. pastoris (designated pG1, SEQ ID NO: 53 which is 100% identical to applicants ECP of SEQ ID NO: 10 see sequence alignment below ), which are regulated by a carbon source other than methanol.
Therefore it would have been obvious to a person of ordinary skill in the art, at the time of the invention to combine the teaching of Brigitte et al with D3-D7, modify the teaching of Brigitte et al by using teaching of the D3 further on the suggestion of one or more art of D4-7 to grow the recombinant host cell which endogenous FLO8 gene of SEQ ID NO: 10 repressed or knocked out ( as taught by Brigitte et al) use the said recombinant host cell expressing gene of protein of interest under control of ECP of SEQ ID NO: 10 ( ass taught by D3). One of skill in the art is motivated to do so because prior at teach that repression of FLO8 protein increase the production expressed protein production the said host cell ( as taught by Brigitte et al) furthermore protein of interest under the control of expression caseate promoter of SEQ ID NO 53 would facilitate more cell growth in the media comprising glucose as carbon source ( as taught by D3).
Double Patenting Rejection
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
This case is a CON of US PAT 11773424. Claims 32-47 of instant application are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims of the US PAT 11773424. An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim not is patentably distinct from the reference claim(s) because the examined claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985). Although the conflicting claims are not identical, they are not patentably distinct from each other.
Claims 32-47 herein and claims 8-12 of US PAT 11773424 are both directed to method of producing a protein of interest (POI) or increasing the yield of a protein of interest (POI) produced by a recombinant host cell wherein expression of an endogenous FLO8 protein is reduced compared to an endogenous expression of said FLO8 protein in a corresponding wild-type host cell, which host cell comprises a heterologous expression cassette comprising a gene of interest (GOI) under control of an expression cassette promoter (ECP) which ECP is not methanol-controlled and repressible by a carbon source that is not methanol, comprising engineering a host cell for reducing said endogenous FLO8 protein expression; and to incorporate said heterologous expression cassette and expressing said GOI under the control of said ECP.
Terminal Disclaimers for the above patent would overcome the rejections
Conclusion
Claims 32-47 are rejected and no claim is allowable.
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/MOHAMMAD Y MEAH/Examiner, Art Unit 1652
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