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 .
Claims Status
Claims 1-46 are pending.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/26/2024 is acknowledged. The submission is in compliance with the provision of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 8 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.
With regards to claim 8, the claim inclusion of “1), 2), 3), and 4)” are awkward in determining if each of the “steps” are required or optional, especially with regard to the placement of “or any” after “4)” therefore rendering the claim indefinite. In the interest of compact prosecution, the Examiner has interpreted the claim for each step to be optional based on the recitation of “or any combination thereof”.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 6, 8, 11-13, 17-20, 23-24, 27-28, 31-35 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi, in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz.
With regards to claims 1-3, Kurachi teaches a method for production of a recombinant protein on an industrial scale (large scale) (see paragraph 0010) using recombinant cells that express the protein under the control of an inducible promoter (see paragraph 0013). Kurachi teaches that the host can be any prokaryote such as Escherichia coli BL21 (see paragraphs 0051 and 0056). Kurachi teaches that the recombinant cells may have a nucleic acid coding for a target protein (see paragraph 0080) and that the target protein can be an antibody fragment or their derivatives (see paragraph 0042). Kurachi teaches that the nucleic acid coding for the target protein can be linked to one or more regulatory sequences that is a sequence that regulates the expression of the recombinant protein in the host, for example, a promoter (see paragraph 0050). Kurachi further teaches that the expression vector used may contain an inducible promoter that allows transcription of the nucleic acid coding for the target protein (see paragraph 0052) and that the inducible promoter functions in the host cell and can regulate transcription based on the presence of an inducer such as an increase or decrease in temperature (see paragraph 0053) or the absence of a repressor molecule. Kurachi teaches that one such inducible promoter can be lambda phase PR promoter which is induced by temperature (see paragraph 0054). Kurachi teaches that the culturing method may be a method of growing recombinant cells by batch culture or fed batch culture, and then dividing the culture solution containing the growing recombinant cells into cells for inducing expression of the recombinant protein and cells for culturing for subsequent regrowth (see paragraph 0084). Kurachi teaches that when the culturing for growth is to be fed batch culture, feeding of the feed substrate containing one or more nutrients of the culture medium may be carried out in a continuous or discontinuous system (see paragraph 0085).
Kurachi teaches that the method includes a step of growing the recombinant cells in a culturing tank by batch culture or fed batch culture (see paragraph 0020). Kurachi teaches a step of transferring a portion of the culture in the culturing tank into a receiving culturing tank after growth in the batch culture step (see paragraph 0021). Kurachi teaches when using a phage PR promoter which is activated by temperature increase, expression of the recombinant protein during growth may be suppressed when the temperature of the culture solution is in the range of 20-37◦ C and expression of the recombinant protein can be induced by increasing the culture solution temperature to 38-44◦ C. Kurachi teaches that as a specific example for the period for initiating induction of expression of the recombinant protein, for recombinant cells wherein the OD600 value at the stationary phase is approximately 150, it is preferrable the period in which the OD600 value has reached 30-110 (see paragraph 0012). Kurarchi further teaches that the recombinant protein is induced in the culturing tank for 10-20 hours (second cultivation temperature) (see paragraph 0095).
Based on the teachings of Kurachi, it would have been obvious to one of ordinary skill in the art of protein engineering prior to the effective filing date of the current instant application to design a process for large scale recombinant production of an antibody fragment and its derivatives (Fc-peptide fusion protein) in recombinant prokaryotic cells by combining a batch phase and feeding phase before induction, and a temperature induction phase wherein the recombinant prokaryotic host cell comprises a nucleic acid encoding the antibody fragment and its derivatives (Fc-peptide fusion protein) that is operably linked to a temperature inducible promoter since Kurachi teaches that the prokaryotic cells have a nucleic acid expressing a target protein that is linked to a promoter that can be a temperature induced promoter. Based on the taught embodiments by Kurachi, one of ordinary skill in the art would have found it obvious to culture the recombinant prokaryotic cells during a batch phase and feeding phase with a first cultivation temperature in the range of 20-37◦ C as taught by Kurachi. One of ordinary skill in the art would have been motivated to select such a temperature range for the batch phase and fed batch phase since Kurachi teaches that this temperature range suppresses expression of the recombinant protein during the cell growth. It would have been further obvious to one of ordinary skill in the art of protein engineering to follow the batch and fed batch phase cultivation by starting a temperature induction phase an OD600 > 30 though a temperature shift in the range of 38-40◦ C since Kurachi teaches that expression of the recombinant protein can be induced by increasing the temperature to 38-44◦ C and that the preferred time to start induction is when the OD600 reading of the cells is with 30-110. It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955). One of ordinary skill in the art of protein engineering would have expectations of success in doing so as Kurachi teaches all of the methods.
With regards to claim 1 and claims 31-35, Kurachi does not specifically teach the recombinant production of an Fc-peptide fusion protein but does teach that the target protein can be an antibody fragment or their derivatives (see paragraph 0080). Kurachi further does not teach that the Fc-peptide is a monomer or dimer, a receptor agonist, a thrombopoietin mimetic, or is romiplostim.
However, Fayaz teaches that romiplostim is a peptibody that has two main parts: peptide sequence which mimics stimulation of thrombopoietin and IgF1Fc (peptide + Antibody=peptibody) (see Abstract, pg. 1). Fayaz further teaches that romiplostim is expressed in E coli BL21 cells (see pg. 2). Fayaz teaches that romiplostim is a dimer or monomer (see Figure 4, pg. 4). Fayaz teaches that romiplostim is a thrombopoietin receptor agonist drug (see conclusion, pg. 5).
It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to select romiplostim as an Fc-peptide to be recombinantly produced bv the process of Kurachi. One of ordinary skill in the art would be motivated to do so since Fayaz teaches that romiplostim is an Fc-peptide fusion protein that can be expressed in E. coli BL21 cells and Kurachi teaches a method for large-scale recombinant production of antibody fragments and their derivatives in E. coli BL21 cells. One of ordinary skill in the art would have expectations of success in doing so as the combined teachings of Fayaz and Kurachi provide all the teachings and methods needed to do so.
With regards to claim 6, in addition to the teachings of Kurachi and Fayaz as applied to claim 1, Kurachi teaches that when using a phage PR promoter which is activated by temperature increase, expression of the recombinant protein during growth may be suppressed when the temperature of the culture solution is in the range of 20-37◦ C. . It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955). It would have therefore been obvious to one of ordinary skill in the art of protein engineering prior to the effective filing date of the current instant application to arrive at a temperature of 30◦ C for the first cultivation. One would be motivated to arrive at this temperature in order to provide a cell growth phase before protein expression is induced as taught by Kurachi. One of ordinary skill in the art would have expectations of success in doing so as Kurachi and Fayaz provide all the necessary teachings.
With regards to claim 8, in addition to the teachings of Kurachi and Fayaz as applied to claim 1, Kurachi does not teach the use methionine in the feeding phase, or an antibiotic in the batch or feeding phase. Furthermore, BL21 E. coli cells are prototrophs, meaning that they can inherently synthesize their own methionine (see abstract, Studier et al. Protein Expression and Purification, vol. 41, pg. 207-234; published April 2005).
With regards to claims 11-12, in addition to the teachings of Kurachi and Fayaz as applied to claim 1, Kurachi teaches that expression of the recombinant protein can be induced by increasing the culture solution temperature to 38-44◦ C and that initiating induction of protein expression of the recombinant protein is preferably the period in which the OD600 value has reached 40-90. It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955). It would have therefore been obvious to one of ordinary skill in the art of protein engineering prior to the effective filing date of the current instant application to start the temperature induction phase at OD600 value of 80-82.5 arrive at a second cultivation temperature of 39◦ C. One of ordinary skill in the art of protein engineering would be motivated to do so since Kurachi teaches a preferred OD600 range to start protein expression and a preferred temperature range to the temperature shift. One of ordinary skill in the art of protein engineering would have expectations of success in doing so since Kurachi and Fayaz provide all the necessary teachings to do so.
With regards to claim 13, in addition to the teachings of Kurachi and Fayaz as applied to claim 1, Kurachi teaches that when using a phage PR promoter which is activated by temperature increase, expression of the recombinant protein during growth may be suppressed when the temperature of the culture solution is in the range of 20-37◦ C and that expression of the recombinant protein can be induced by increasing the culture solution temperature to 38-44◦ C. It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955). It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to arrive at a first cultivation temperature of 30◦ C and a second cultivation temperature of 39◦ C since Kurachi teaches that during cell growth at a temperature range of 20-37◦ C, protein expression would be suppressed allowing for cell growth and that protein expression can be induced within the temperature range of 38-44◦ C. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Kurachi and Fayaz.
With regards to claims 17-20, in addition to the teachings of Kurachi and Fayaz as applied to claim 1, Kurachi teaches that the main culture medium loading in a culturing tank (bioreactor) (see paragraph 0138 and 0139) where aerated stirring was carried out so that the dissolved oxygen in the culture solution was maintained at 30-40% dissolved oxygen saturation (see paragraph 0139).
With regards to claim 23, in addition to the teachings of Kurachi and Fayaz as applied to claim 1, Fayaz teaches that romiplostim (Fc-peptide fusion protein) is expressed as an inclusion body (see abstract pg. 1 and Figure 4, pg. 3).
With regards to claim 24 and 28, in addition to the teachings of Kurachi and Fayaz as applied to claim 1, Kurachi teaches that after induction of the recombinant protein for the prescribed time period, the culture solution is transferred to a separation purification tank where the expressed recombinant protein is separated and purified (see paragraph 0096).
With regards to claim 27, in addition to the teachings of Kurachi and Fayaz as applied to claims 1 and 24, although Kurachi does not teach a refolding step of the produced recombinant protein, Fayaz teaches that romiplostim (Fc-peptide fusion protein) accumulates in inclusion bodies (see Abstract, pg. 1). Fayaz teaches that the solubilized romiplostim is subjected to a refolding step (see pg. 3). It would have therefore been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to use the refolding protocol taught by Fayaz to refold any Fc-peptide fusion protein isolated from inclusion bodies accumulated during the recombinant protein production process taught by Kurachi and Fayaz. One of ordinary skill in the art would be motivated by the teachings of Fayaz to use the refolding procedure to obtain properly folded protein for subsequent use. One of ordinary skill in the art would have expectations of success in doing so as the combined teachings of Kurachi and Fayaz provide the necessary guidance to do so.
Therefore, claims 1-3, 6, 8, 11-13, 17-20, 23-24, 27-28, 31-35 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785).
Claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi, in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, as applied to claim 1 above, and further in view of Villaverde et al. (Applied and Environmental Microbiology, Vol. 59, pg. 3485-3487, published October 1993), hereinafter referred to as Villaverde.
The teachings of Kurachi and Fayaz as applied to claim 1 is summarized above.
With regards to claims 4-5, Kurachi does teach the expression vector used may contain an inducible promoter that allows transcription of the nucleic acid coding for the target protein (see paragraph 0052) and that the inducible promoter functions in the host cell and can regulate transcription based on the presence of an inducer such as an increase or decrease in temperature (see paragraph 0053) or the absence of a repressor molecule. Kurachi teaches that one such inducible promoter can be lambda phase PR promoter which is induced by temperature (see paragraph 0054).
However, neither Kurachi or Fayaz teach that the temperature sensitive repressor that regulates lambda PR is lambda cI857 repressor.
However, Villaverde teaches the that strong PR lambda promoters used in combination with the CI857 repressor are usually induced by a temperature shift from 30-42◦ C and that this is very convenient for scaled up production of heterologous proteins in bioreactors (see pg. 3485).
Therefore, it would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to use a temperature inducible promoter that is a lambda PR promoter which is regulated by a temperature sensitive repressor that is lambda CI857 repressor taught by Villaverde as the temperature induced promoter in the recombinant prokaryotic host cell taught by Kurachi and Fayaz. One of ordinary skill in the art would be motivated to do so since Villaverde teaches that strong PR lambda promoters used in combination with the cI857 repressor are induced by a temperature shift from 30 to 42◦ C and that this provides for convenient scaled up production of heterologous proteins in bioreactors. One of ordinary skill in the art of protein engineering would have expectations of success in doing so from the combined teachings of Kurachi, Fayaz, and Villaverde who provide all the necessary teachings and guidance needed to do so.
Therefore, claims 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), as applied to claim 1 above, and further in view of Villaverde et al. (Applied and Environmental Microbiology, Vol. 59, pg. 3485-3487, published October 1993).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi and in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, as applied to claim 1 above, and further in view of Mitchell et al. (Applied Microbiology, Vol. 1, pg. 239-254, published July 16, 2021), hereinafter referred to as Mitchell.
The teachings of Kurachi and Fazyaz as applied to claim 1 are summarized above.
With regards to claim 7, neither Kurachi or Fayaz teach that the culturing of the recombinant prokaryotic host occurs in the presence of glycerol as a carbon source.
However, Mitchell teaches the use of glycerol as a carbon source in E. coli chemostat cultures. Mitchell teaches that as a by-product of biodiesel production, glycerol is expected to become a sustainable alternative substrate to glucose (see Abstract, pg. 239).
It would have been obvious to one of ordinary skill in the art of protein engineering and expression before the effective filing date of the current instant application to use glycerol as a carbon source in the recombinant protein production taught by Kurachi and Fayaz. One of ordinary skill in the art would be motivated to do so since Mitchell teaches that glycerol can serve as a sustainable alternative carbon source to glucose. One of ordinary skill in the art would have expectations of success in doing from the combined teachings of Kurachi, Fayaz, and Mitchell who provide all the necessary teachings and guidance to do so.
Therefore, claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) as applied to claim 1 above, and further in view of Mitchell et al. (Applied Microbiology, Vol. 1, pg. 239-254, published July 16, 2021).
Claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, as applied to claim 1 above, and further in view of Metha et al. (United States Patent No. US 6,627,438 B2; published September 30, 2003), hereinafter referred to as Metha.
The teachings of Kurachi and Fayaz as applied to claim 1 are summarized above.
With regards to claims 9-10, neither Kurachi or Fayaz teach that when culturing the recombinant prokaryotic host cells according to step a, it occurs at a growth rate of 0.05 to 0.3 doublings per hour or that the growth rate is 0.1 doublings per hour.
However, Metha teaches the expression of peptide products into culture media where genetically engineered host cells are grown (see Abstract). Metha teaches that improved yield of peptide product is obtained by carefully controlling the average cell growth rate within a critical range between 0.05 to 0.20 doublings per hour. Metha teaches that it is preferred that this controlled growth rate begin in the early lag phase of the culture and that it is more preferable to maintain average cell growth rate during the fermentation period between 0.10 and 0.15 doublings per hour (see column 10, lines 35-44). It is well settled that discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955)”.
It would have been obvious to one of ordinary skill in the art of protein engineering and expression before the effective filing date of the current instant application to incorporate an average growth rate between 0.05 and 0.20 doublings per hour in the recombinant protein production process taught by Kurachi and Fayaz. One of ordinary skill in the art would be motivated to do so since Metha teaches that controlling the average growth rate within this range provides the benefit of improved yield of peptide product. One of ordinary skill in the art would have expectations of success in doing so as the combined teachings of Kurachi, Fayaz, and Metha provide all the teachings, methods, and guidance needed to do so.
Therefore, claims 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) as applied to claim 1 above, and further in view of Metha et al. (United States Patent No. US 6,627,438 B2; published September 30, 2003).
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi, in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, as applied to claim 1 above, and further in view of Nakahigashi et al. (US Patent Application Publication No. US 2022/0033870 A1; published February 3, 2022), hereinafter referred to as Nakahigashi.
The teachings of Kurachi and Fayaz as applied to claim 1 is summarized above.
With regards to claims 14-16, neither Kurachi or Fayaz specifically teach a second cultivation temperature of 5-10, 6-8 hours, or 8 hours.
However, Nakahigashi teaches a production method for a recombinant protein (see paragraph 0001) in E. coli BL21 cells (see paragraph 0126). Nakahigashi teaches that the recombinant protein can be an antibody fragment or derivative (see paragraph 0074). Nakahigashi teaches that expression of the recombinant protein can be induced by increasing the temperature of the culture solution to 39-44 C (see paragraph 0111) and that the culturing time can be 1-60 hours (see paragraph 0104) and that culturing conditions are not particularly limited so long as the recombinant cells can grow and the target protein can be accumulated in the recombinant cells which express the recombinant protein (see paragraph 0105). It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955).
It would have been obvious to one of ordinary skill in the art of protein engineering prior to the effective filing date of the current instant application to arrive at a maintained second cultivation temperature of either 5-10 hours, 6-8 hours, or 8 hours since Nakahigashi teaches that the culturing time can be 1-60 hours. One of ordinary skill in the art would be motivated by the teachings of Nakahigashi to optimize the time the second cultivation temperature is maintained based on the range of time taught by Nakahigashi in order to allow sufficient time for cell growth and protein production. One of ordinary skill in the art would have expectations of success in doing from the combined teachings of Kurachi, Fayaz, and Nakahigashi who provide all the necessary teachings and guidance needed to do so.
Therefore, claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) as applied to claim 1 above, and further in view of Nakahigashi et al. (US Patent Application Publication No. US 2022/0033870 A1; published February 3, 2022).
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi, in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, as applied to claim 17 above, and further in view of Lopes et al. (Biotechnology Progress, Vol. 30, pg. 767-775, published online July 21, 2014), hereinafter referred to as Lopes.
The teachings of Kurachi and Fayaz as applied to claim 17 is summarized above.
With regards to claims 21-22, neither Kurachi or Fayaz specifically teach that the dissolved oxygen concentration is maintained through control of a bioreactor pressure or that the bioreactor pressure is increased from 0.0 to 0.8 bar(g).
However, Lopes teaches that aerobic bioprocess are generally carried out in aqueous media where the solubility of oxygen is low (see pg. 767). Lopes further teaches that in industrial biotechnology, microbial cultures are exposed to different local pressure inside bioreactors (see Abstract, pg. 767). Lopes also teaches that adequate oxygen supply in crucial to the growth and maintenance of most aerobic microbial cultures (see pg. 767). Lopes further teaches that the use of increased air pressure in bioreactors leads to an increase in dissolve oxygen (see pg. 773). Lopes also teaches increased air pressure on microbial cultures under moderate total pressure conditions (maximum 15 bar). It is well settled that “discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art. In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980) and where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 220 F2d 454, 456, 105 USPQ 233; 235 (CCPA 1955).
It would have been obvious to one of ordinary skill in the art of protein expression before the effective filing date of the current instant application to control the dissolved oxygen concentration in the recombinant protein production method taught by Kurachi and Fayaz through a bioreactor and increasing the pressure as taught by Lopes since Lopes teaches that increasing the air pressure inside the bioreactor can lead to an increase in dissolved oxygen. One of ordinary skill in the art would also be able to arrive at an increase pressure value of 0.8 through routine optimization since Lopes teaches a workable range of pressure. One would be motivated by the teachings of Lopes who teaches that adequate supply of oxygen to the medium is crucial for microbial growth. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Kurachi, Fayaz, and Lopes who provide all the necessary teachings and guidance to do so.
Therefore, claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) as applied to claim 17 above, and further in view of Lopes et al. (Biotechnology Progress, Vol. 30, pg. 767-775, published online July 21, 2014).
Claims 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi, in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, as applied to claim 1 above, and further in view of Margreiter et al. (Vol. 138, pg. 67-73, published August 8, 2008; PMID: 18760314), hereinafter referred to as Margreiter.
The teachings of Karuchi and Fayaz as applied to claims 1 and 24 are summarized above.
With regards to claims 25-26, neither Kurachi or Fayaz teach the isolation of a Fc-peptide fusion protein containing inclusion bodies by a sedimentation step.
However, Margreiter teaches that Escherichia coli is commonly used as a host to express recombinant proteins, however, one phenomenon frequently observed is that many heterologous proteins become incorrectly folded and form the so-called inclusion bodies (IBs) (see pg. 67). Margreiter teaches that because IBs are mechanically unstable, they can be isolated from cells and separated by centrifugation (sedimentation) once they have reached adequate mass (see pg. 67).
It would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to use a sedimentation step such as centrifugation taught by Margreiter to separate the Fc-peptide fusion protein from the inclusion bodies accumulated during the recombinant protein production from the combined teachings of Kurachi and Fayaz. One of ordinary skill in the art would be motivated to use centrifugation as an isolation step since Margreiter teaches that centrifugation is effective in isolating inclusion bodies from cells. One of ordinary skill in the art of protein purification would have expectations of success in doing so since Kurachi, Fayaz, and Margreiter teach all the methods needed to do so.
Therefore, claims 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) as applied to claim 1 above, and further in view of Margreiter et al. (Vol. 138, pg. 67-73, published August 8, 2008; PMID: 18760314).
Claims 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi, in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, as applied to claim 24 above, and further in view of Baeck et al. (Journal of Membrane Science. Vol. 528, pg. 171-177, published 2017), hereinafter referred to as Baeck, and further in view of Zhang et al. (Protein Expression and Purification, Vol. 164: 105458; published 2019), hereinafter referred to as Zhang.
The teachings of Kurachi and Fayaz as applied to claim 24 is taught above.
With regards to claims 29-30, neither Kurachi or Fayaz teach a purification process for purifying the Fc-peptide fusion protein outlined in instant claim 29 (affinity capture chromatography, mixed-mode chromatography, cation exchange chromatography, ultrafiltration/diafiltration).
However, Baeck teaches that Fc-fusion proteins are important new class of biotherapeutics (see Abstract, pg. 171). Baeck teaches that purification of Fc-fusion proteins typically follows a platform that is used for monoclonal antibodies beginning with a Protein A affinity chromatography followed by appropriate polishing steps and then formulation by ultrafiltration/diafiltration (see pg. 171). Baeck does not specifically teach polishing steps of mixed-mode chromatography or cation exchange chromatography.
However, Zhang teaches that Protein A chromatography is routinely used for antibody capture and initial purification (see pg. 1). Zhang teaches that Protein A chromatography capture step is normally followed by cation exchange or anion exchange chromatography (see pg. 1). Zhang further teaches replacing mixed-mode chromatography as the subsequent step following Protein A chromatography in the bind-elute mode (see pg. 1). Zhang teaches that the mixed-mode resin CHT is best known for its superior ability to reduce antibody aggregates (see pg. 4). Zhang also teaches the use of 2 wash steps in the Protein A chromatography and mixed mode chromatography steps (see Tables 1 and 2, pg. 2).
It would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to use a purification procedure for the Fc-peptide fusion protein obtained from the teachings of Kurachi and Fayaz that involves: 1) Protein A capture affinity chromatography in bind-elute mode (including 2 wash steps), 2) mixed-mode chromatography in bind-elute mode( including 2 wash steps), followed by an additional polishing step using 3) cation exchange chromatography in bind-elute mode, followed by final formulation by ultrafiltration/diafiltration as taught by the combined teachings of Baeck and Zhang. One of ordinary skill in the art would be motivated by the teachings of Baeck and Zhang who teach that Protein A capture chromatography is generally the first step in purification of Fc-fusion proteins that can be followed by additional polishing steps such as mixed-mode chromatography, cation-exchange chromatography, and ultrafiltration/diafiltration in order to improve the purity of the Fc-peptide fusion protein for therapeutic use. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Kurachi, Fayaz, Baeck, and Zhang who teach all the necessary methods needed to do so.
Therefore, claims 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) as applied to claim 24 above, and further in view of Baeck et al. (Journal of Membrane Science. Vol. 528, pg. 171-177, published 2017) and further in view of Zhang et al. (Protein Expression and Purification, Vol. 164: 105458; published 2019).
Claims 36 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, and in further view of Gadgil et al. (US Patent No. US 10,918,698 B2; published February 16, 2021), hereinafter referred to as Gadgil.
Kurachi teaches a method for production of a recombinant protein on an industrial scale (large scale) (see column 1, paragraph 0010) using recombinant cells that express the protein under the control of an inducible promoter (see column 1, paragraph 0013). Kurachi teaches that the host can be any prokaryote such as Escherichia coli BL21 (see column 2, paragraphs 0051 and 0056). Kurachi teaches that the recombinant cells may have a nucleic acid coding for a target protein (see column 5, paragraph 0080) and that the target protein can be an antibody fragment or their derivatives (see column 2, paragraph 0042). Kurachi teaches that the nucleic acid coding for the target protein can be linked to one or more regulatory sequences that is a sequence that regulates the expression of the recombinant protein in the host, for example, a promoter (see paragraph 0050). Kurachi further teaches that the expression vector used may contain an inducible promoter that allows transcription of the nucleic acid coding for the target protein (see paragraph 0052) and that the inducible promoter functions in the host cell and can regulate transcription based on the presence of an inducer such as an increase or decrease in temperature (see paragraph 0053) or the absence of a repressor molecule. Kurachi teaches that one such inducible promoter can be lambda phase PR promoter which is induced by temperature (see paragraph 0054). Kurachi teaches that the culturing method may be a method of growing recombinant cells by batch culture or fed batch culture, and then dividing the culture solution containing the growing recombinant cells into cells for inducing expression of the recombinant protein and cells for culturing for subsequent regrowth (see column 5, paragraph 0084). Kurachi teaches that when the culturing for growth is to be fed batch culture, feeding of the feed substrate containing one or more nutrients of the culture medium may be carried out in a continuous or discontinuous system (see column 5, paragraph 0085).
Kurachi teaches that the method includes a step of growing the recombinant cells in a culturing tank by batch culture or fed batch culture (see column 1, paragraph 0020). Kurachi teaches a step of transferring a portion of the culture in the culturing tank into a receiving culturing tank after growth in the batch culture step (see column 1, paragraph 0021). Kurachi teaches when using a phage PR promoter which is activated by temperature increase, expression of the recombinant protein during growth may be suppressed when the temperature of the culture solution is in the range of 20-37◦ C and expression of the recombinant protein can be induced by increasing the culture solution temperature to 38-44◦ C. Kurachi teaches that as a specific example for the period for initiating induction of expression of the recombinant protein, for recombinant cells wherein the OD600 value at the stationary phase is approximately 150, it is preferrable the period in which the OD600 value has reached 30-110 (see paragraph 0012). Kurarchi further teaches that the recombinant protein is induced in the culturing tank for 10-20 hours (second cultivation temperature) (see paragraph 0095). Kurachi further teaches after induction of the recombinant protein for the prescribed time period, the culture solution is transferred to a separation purification tank where the expressed recombinant protein is separated and purified (see paragraph 0096).
Based on the teachings of Kurachi, it would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to design a process for large scale recombinant production of an antibody fragment and its derivatives (Fc-peptide fusion protein) in recombinant prokaryotic cells by combining a batch phase and feeding phase before induction, and a temperature induction phase wherein the recombinant prokaryotic host cell comprises a nucleic acid encoding the antibody fragment and its derivatives (Fc-peptide fusion protein) that is operably linked to a temperature inducible promoter since Kurachi teaches that the prokaryotic cells have a nucleic acid expressing a target protein that is linked to a promoter that can be a temperature induced promoter. Based on the taught embodiments by Kurachi, one of ordinary skill in the art would have found it obvious before the effective filing date of the current instant application to culture the recombinant prokaryotic cells during a batch phase and feeding phase with a first cultivation temperature in the range of 20-37◦ C as taught by Kurachi. One of ordinary skill in the art would have been motivated to select such a temperature range for the batch phase and fed batch phase since Kurachi teaches that this temperature range suppresses expression of the recombinant protein during the cell growth. It would have been further obvious to one of ordinary skill in the art of protein engineering to follow the batch and fed batch phase cultivation by starting a temperature induction phase an OD600 > 30 though a temperature shift in the range of 38-40◦ C since Kurachi teaches that expression of the recombinant protein can be induced by increasing the temperature to 38-44◦ C and that the preferred time to start induction is when the OD600 reading of the cells is with 30-110. One of ordinary skill in the art of protein engineering would have expectations of success in doing so as Kurachi teaches all of the methods needed to do so.
With regards to claim 36, Kurachi does not specifically teach the recombinant production of an Fc-peptide fusion protein but does teach that the target protein can be an antibody fragment or their derivatives (see paragraph 0080). Kurachi further does not teach that the Fc-peptide is romiplostim.
However, Fayaz teaches that romiplostim is a peptibody that has two main parts: peptide sequence which mimics stimulation of thrombopoietin and IgF1Fc (peptide + Antibody=peptibody) (see Abstract, pg. 1). Fayaz further teaches that romiplostim is expressed in E coli BL21 cells (see pg. 2).
It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to select romiplostim as an Fc-peptide to be recombinantly produced bv the method of Kurachi. One of ordinary skill in the art would be motivated to do so since Fayaz teaches that romiplostim is an Fc-peptide fusion protein that can be expressed in E. coli BL21 cells and Kurachi teaches a method for large-scale recombinant production of antibody fragments and their derivatives in E. coli BL21 cells. One of ordinary skill in the art would have expectations of success in doing so as the combined teachings of Fayaz and Kurachi provide all the teachings and methods needed to do so.
With regards to claims 36 and 38, neither Kurachi or Fayaz teach that the Fc-peptide fusion protein is manufactured into a pharmaceutical composition or teach the formulation of the Fc-peptide fusion with a pharmaceutically acceptable carrier or buffer or that the pharmaceutical composition is lyophilized.
However, Gadgil teaches an invention to provide a stable lyophilized pharmaceutical composition of a Fc-peptide fusion protein comprising a buffer system selected from the group of citrate, citro-phosphate, alanine, glycine….. or a combination thereof (see column 3, lines 1-5).
It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to prepare the Fc-peptide fusion protein produced by the method taught by Kurachi and Fayaz by lyophilizing the Fc-peptide fusion and preparing a pharmaceutical composition of the lyophilized Fc-peptide with a buffer system taught by Gadgil. One of ordinary skill in the art would be motivated to do so in order to provide a stable composition of the produced Fc-peptide fusion protein for pharmaceutical use. One of ordinary skill in the art would have expectations of success in doing so since Kurachi, Fayaz, and Gadgil provide all the necessary teachings and guidance to do so.
Therefore, claims 36 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) and further in view of Gadgil et al. (US Patent No. US 10,918,698 B2; published February 16, 2021).
Claims 37, 41, 42, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz, further in view of Gadgil et al. (US Patent No. US 10,918,698 B2; published February 16, 2021), hereinafter referred to as Gadgil, as applied to claim 36 above, and further in view of Hubulashvili et al. (P&T, Volume 34, pg. 482-485; published September 2009), hereinafter referred to as Hubulashvili.
The teachings of Kurachi, Fayaz, and Gadgil as applied to claim 36 is summarized above.
With regards to claims 37 and 41-43, neither Kurachi, Fayaz, or Gadgil teach that the pharmaceutical composition is in the form of a sterile and preservative-free white powder or that the pharmaceutical composition is stored in a pharmaceutical container as a single-dose vial.
However, Hubulashvili teaches that romiplostim is supplied as a preservative-free white powder in 250 or 500 mcg vials for single use. (see pg. 484)
It would have been obvious to one of ordinary skill in the art of protein purification before the effective filing date of the current instant application to formulate the purified Fc-peptide fusion (romiplostim) produced by the process taught by Kurachi and Fayaz in a preservative free white powder that is stored in a single-use vial as taught by Hubulashvili. One of ordinary skill in the art would be motivated by the teachings of Hubulashvili who provide teachings on how romiplostim is formulated for therapeutic use. One of ordinary skill in the art would have expectations of success in doing so from the combined teachings of Kurachi, Fayaz, and Hubulashvili who provide all the teachings and guidance needed to do so.
Hubulashvili further teaches that the product is reconstituted with preservative-free sterile water for injection which indicates that the white powder is inherently sterile.
Therefore, claims 37, 41, 42, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) and further in view of Gadgil et al. (US Patent No. US 10,918,698 B2; published February 16, 2021) as applied to claim 36 above, and further in view of Hubulashvili et al. (P&T, Volume 34, pg. 482-485; published September 2009).
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz,. and in further view of Gadgil et al. (US Patent No. US 10,918,698 B2; published February 16, 2021), hereinafter referred to as Gadgil, as applied to claim 36 above, and further in view of Wang et al. (Antibody Therapeutics, Vol. 4, pg. 262-273, published 2021), hereinafter referred to as Wang.
The teachings of Kurachi, Fayaz, and Gadgil as applied to claim 36 are summarized above.
Neither Kurachi, Fayaz, or Gadgil teach that the pharmaceutical composition further comprises L-histidine, mannitol, polysorbate 20, sucrose, and HCl.
However, Wang teaches that 34 of the total US FDA approved 103 therapeutic antibody drugs are formulated with high protein concentrations (see Abstract, pg. 262). Wang teaches that it may be rational to implement a platform formulation containing polysorbate, histidine, and sucrose to accelerate high protein concentration formulation development for antibody drugs (see Abstract, pg. 262). Wang further teaches that major formula excipients include polysorbate 20, histidine and sucrose and other formulations include mannitol and histidine-HCl is the dominant buffer used. (see pg. 263 and 269).
It would have therefore been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to further include L-histidine, mannitol, polysorbate 20, sucrose, and HCl in the pharmaceutical composition as beneficial pharmaceutical excipients since Wang teaches that these are the most common excipients observed in FDA approved antibody therapeutics. One of ordinary skill in the art would be motivated by the teachings of Wang to include such excipients in the pharmaceutical composition as it may be beneficial in achieving high protein concentration. One of ordinary skill in the art would have expectations of success in doing so as the combined teachings of Kurachi, Fayaz, Gadgil, and Wang provide all the necessary teachings and guidance to do so.
Therefore, claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) and further in view of Gadgil et al. (US Patent No. US 10,918,698 B2; published February 16, 2021) as applied to claim 36 above, and further in view of Wang et al. (Antibody Therapeutics, Vol. 4, pg. 262-273, published 2021).
Claims 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019), hereinafter referred to as Kurachi in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785), hereinafter referred to as Fayaz et al. and further in view of Gadgil et al. (US Patent No. US 10,918,698 B2; published February 16, 2021), hereinafter referred to as Gadgil, and further in view of Hubulashvili et al. (P&T, Volume 34, pg. 482-485; published September 2009), hereinafter referred to as Hubulashvili, as applied to claim 43 above, and further in view of FDA labeling information (Nplate, Romiplostim, pg. 1-10, Initial US Approval 2008, Revised 11/2012), hereinafter referred to as FDA.
With regards to claim 44, neither Kurachi, Fayaz, Gadgil, or Hubulashvili teach that the single-dose vial comprises the components listed in instant claim 44.
However, FDA teaches that romiplostim (Nplate) for injection is supplied as a sterile, preservative free lypholized white powder for subcutaneous injection. FDA teaches that each single-dose 125 mcg vial of Nplate (romiplostim) contains 230 mg romiplostim, 0.7 mg L-histidine, 18 mg mannitol, 0.02 mg polysorbate 20, 9 mg sucrose, and sufficient HCL to adjust the pH to a target of 5.0 (see pg. 7).
It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to comprise the single-dose vial with 125 mcg vial of Nplate (romiplostim) contains 230 mg romiplostim, 0.7 mg L-histidine, 18 mg mannitol, 0.02 mg polysorbate 20, 9 mg sucrose, and sufficient HCL to adjust the pH to a target of 5.0 as taught by FDA. One would be motivated to do so since FDA teaches that this is how romiplostim is supplied in single-dose vials for subcutaneous injection. One of ordinary skill in the art of would have expectations of success in doing so since Kurachi, Fayaz, Gadgil, Hubulashvili, and FDA provide all the teachings and guidance needed to do so.
With regards to claim 45, neither Kurachi, Fayaz, Gadgil, or Hubulashvili teach that the single-dose vial comprises the components listed in instant claim 45.
However, FDA teaches that romiplostim (Nplate) for injection is supplied as a sterile, preservative free lyopholized white powder for subcutaneous injection. FDA teaches that each single-dose 250 mcg vial of Nplate (romiplostim) contains 375 mg romiplostim, 1.2 mg L-histidine, 30 mg mannitol, 0.03 mg polysorbate 20, 15 mg sucrose, and sufficient HCL to adjust the pH to a target of 5.0 (see pg. 7).
It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to comprise the single-dose vial with 375 mg romiplostim, 1.2 mg L-histidine, 30 mg mannitol, 0.03 mg polysorbate 20, 15 mg sucrose, and sufficient HCL to adjust the pH to a target of 5.0 (see pg. 11) as taught by FDA. One would be motivated to do so since FDA teaches that this is how romiplostim is supplied in single-dose vials for subcutaneous injection. One of ordinary skill in the art of would have expectations of success in doing so since Kurachi, Fayaz, Gadgil, Hubulashvili, and FDA provide all the teachings and guidance needed to do so.
With regards to claim 46, neither Kurachi, Fayaz, Gadgil, or Hubulashvili teach that the single-dose vial comprises the components listed in instant claim 45.
However, FDA teaches that romiplostim (Nplate) for injection is supplied as a sterile, preservative free lypholized white powder for subcutaneous injection. FDA teaches that each single-dose 250 mcg vial of Nplate (romiplostim) contains 625 mg romiplostim, 1.9 mg L-histidine, 50 mg mannitol, 0.05 mg polysorbate 20, 25 mg sucrose, and sufficient HCL to adjust the pH to a target of 5.0 (see pg. 7).
It would have been obvious to one of ordinary skill in the art of protein engineering before the effective filing date of the current instant application to comprise the single-dose vial with 625 mg romiplostim, 1.9 mg L-histidine, 50 mg mannitol, 0.05 mg polysorbate 20, 25 mg sucrose, and sufficient HCL to adjust the pH to a target of 5.0 as taught by FDA. One would be motivated to do so since FDA teaches that this is how romiplostim is supplied in single-dose vials for subcutaneous injection. One of ordinary skill in the art of would have expectations of success in doing so since Kurachi, Fayaz, Gadgil, Hubulashvili, and FDA provide all the teachings and guidance needed to do so.
Therefore, claims 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Kurachi et al (US Patent Application Publication No. US 2019/0194710 A1; published June 27, 2019) in view of Fayaz et al. (DARU Journal of Pharmaceutical Sciences, Vol. 24:18, published July 11, 2016, PMID: 27401785) and further in view of Gadgil et al. (US Patent No. US 10,918,698 B2; published February 16, 2021) and further in view of Hubulashvili et al. (P&T, Volume 34, pg. 482-485; published September 2009) as applied to claim 43 above, and further in view of further in view of FDA labeling information (Nplate, Romiplostim, pg. 1-10, Initial US Approval 2008, Revised 11/2012).
Conclusion
No claims are allowed.
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/GEORGE THEMISTOCLIS LOUNTOS/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652
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