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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/9/2025 has been entered.
In the submission, no claims are amended. Accordingly, claims 1, 2, 4-9, 15 and 25-33 are pending and under current examination.
Priority
This application is a division of U.S. Patent Application No. 16/026,539, filed July 3, 2018, which claims benefit to prior-filed U.S. provisional patent applications 62/529,471 (filed 07/06/2017) and 62/625,744 (filed 02/02/2018).
Status of Prior Rejection/Response to Arguments
The rejection of claims 1-2, 4-9, 15 and 25-33 under 35 U.S.C. 112(a) is withdrawn:
Applicant asserts that U.S. Provisional Application Nos. 62/625,744 and 62/529,471 recite a soy hydrolysate comprising 0.003%- 0.027% (w/w) ornithine. Accordingly, the limitation of 0.003%-0.027% (w/w) ornithine as recited by the instant claims is disclosed in the application and complies with the written description requirement (Remarks, p5).
Applicant’s argument is found persuasive. The rejection is withdrawn.
The rejections of claims 1-2, 4-7 and 32-33 under 35 U.S.C. § 103 over Kang et al. in view of Krishnan et al., Richardson et al. and Richardson et al. is withdrawn:
The rejection of claims 1-2, 4-9, 15, 25-33 under 35 U.S.C. § 103 over Kang et al. in view of Krishnan et al., Richardson et al., Engel et al. and Rohrer et al. is withdrawn:
Applicant traverses the rejection, alleges that: (1) Kang does not teach or suggest steps (a)-(b) of instant claim 1, Kang contains no recognition that soy hydrolysates might vary from batch to batch, or that soy hydrolysates should be screened for any component, much less for 0.003%- 0.027% (w/w) ornithine as recited by instant claim 1 (Remarks, p7); (2) Krishnan does not remedy the deficiencies of Kang. Krishnan teaches a cell culture medium comprising soy hydrolysate, and a specific concentration of ornithine (Remarks, p7); (3) Richardson does not remedy the combined deficiencies of Kang and Krishnan, Richardson is silent on the specific amount of ornithine in the soy hydrolysate added to the culture medium. The concentrations of ornithine in the culture media taught by Richardson (90 µM and 760 µM) are amounts of ornithine that were spiked into the media, that is, pure ornithine supplemented into the media (Remarks, p8).
Applicant’s argument is found persuasive. Specifically, both Kang and Krishnan teach using soy hydrolysates in the culture medium AND providing extra ornithine (see parag 0134 of Kang and parag 0006 of Krishnan), but not teach using the soy hydrolysates to provide the ornithine. Richardson teach the soy hydrolysates containing ornithine and other amino acids and organic acids. One of ordinary skill would have been reasonably appraised by the teachings to use soy hydrolysates containing ornithine to achieve a certain concentration of ornithine in the culture medium (i.e., the concentration showed in figure 7 of Kang, or the concentration showed in parag 0006 of Krishnan) for the production of a recombinant heterologous glycoprotein, but would not have been inspired to have a step of “selecting a soy hydrolysate comprising 0.003% - 0.027% (w/w) ornithine” before adding the soy hydrolysate in the culture medium. Therefore the rejection is withdrawn.
New grounds of rejection are made after re-considering the scope of instant claims.
Claim Rejections - 35 USC § 112(a)
Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—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 or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 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 1-2, 4-9, 15 and 25-33 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
From M.P.E.P. § 2163, the analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention from the standpoint of one of skill in the art at the time the application was filed. For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. For claims drawn to a genus, possession may be shown (for example) through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A “representative number of species” means that the species which are adequately described are representative of the entire genus, and is an inverse function of the skill and knowledge in the art. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to
reflect the variation within the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, para. 1.
Instant claim 1 is directed to a method comprising determining and selecting a soy hydrolysate comprising 0.003%-0.027% (w/w) ornithine, and culturing a population of cells expressing a recombinant heterologous glycoprotein in a cell culture medium comprising said soy hydrolysate to produce the recombinant heterologous glycoprotein. Claim 1 encompasses a genus of recombinant heterologous glycoprotein, which can be produced by various heterologous host cells (such as bacterial, yeast, insect cells or mammalian cells) and comprising different sugar structures such as N-linked, O-linked, or modified glycosylation. Wherein, for instance, the N-linked glycoprotein further comprises various species such as Sialic Acids, G0F, G0 and man5, G1F, G1F-GlcNAc and G2F (see i.e., figure 2 and table 1 of Hamm et al. (Pharmaceuticals 2013, 6, 393-406)). Therefore the claim is extremely board. Claims 6, 28 and 30 further limit the type of recombinant heterologous glycoprotein is a trap molecule, as well as a specific trap molecule rilonacept or aflibercept. The issue at hand is whether or not Applicant has possession of the full scope of the method.
In the instant case, Applicant has failed to provide disclosure of full scope of the method of producing the genus of recombinant heterologous glycoprotein using a culture medium comprising a soy hydrolysate comprising 0.003% - 0.027% (w/w) ornithine. The disclosure provides working examples regarding using soy hydrolysate comprising between 0.067 and 0.67 mg ornithine per g (which is 0.0067% - 0.067% (w/w)) soy to produce a trap protein (receptor-Fc fusion protein, VEGF-trap), comprising screening soy hydrolysate to determine the concentration of ornithine (0.067 and 0.67 mg ornithine per g soy, Example 1), and using CHO cells to express VEGF-trap in a culture medium with said soy hydrolysate, wherein the final concentration of ornithine is less than 5.0 mg/L (as well as 6.6 mg/L and 31.6 mg/L as showed in table 2), demonstrating that soy hydrolysate with an ornithine concentration of 2.0 mg/L or less produce higher quality protein product (measured by the higher production of A1 N-glycan) and more consistent A1 N-glycan protein production (Example 2). The disclosure further shows that glycoprotein production and titer is correlated with ornithine in the soy hydrolysate (Example 3 and Example 4). Applicant does not disclose the production of any other species of the recombinant heterologous glycoprotein by the claimed method. Thus Applicant failed to disclose the production of a genus of recombinant heterologous glycoprotein by using ornithine provided by a soy hydrolysate comprising 0.003% - 0.027% (w/w) ornithine in the culture medium which can represent the full scope of instant claim 1.
Furthermore, Applicant has failed to provide disclosure of relevant, identifying characteristics, such as the functional characteristics (production of a genus of recombinant heterologous glycoprotein comprising higher A1 N-glycan level) coupled with known or disclosed structure of the soy hydrolysate comprising 0.003% - 0.027% (w/w) ornithine. In instant case, the working examples only disclose the production of VEGF-trap glycoprotein with an ornithine final concentration of less than 5.0 mg/L (i.e., 2.0 mg/L or less), wherein the ornithine is provided by the soy hydrolysate comprising 0.003% - 0.027% (w/w) ornithine, but failed to establish a known structure- function relationship wherein the genus of structures of a soy hydrolysate comprising 0.003% - 0.027% (w/w) ornithine is capable of producing a genus of recombinant heterologous glycoprotein comprising higher A1 N-glycan level as claimed with any predictability. Thus, one of ordinary skill in the art, in looking to the instant specification, would not be able to determine that Applicant was in possession of the invention, as claimed, at the time the invention was made.
Claims 2, 4-9, 15 and 25-33 depend from, at least, claim 1, and thus inherit the deficiency and are rejected on the same basis.
Claim Rejections - 35 USC § 112
Scope of Enablement
Claims 1, 2, 4-9, 15 and 25-33 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling a method comprising determining and selecting soy hydrolysate comprising 0.003%-0.027% (w/w) ornithine, and culturing a population of cells expressing VEGF trap glycoprotein in a cell culture medium comprising said soy hydrolysate with a ornithine final concentration of less than 5.0 mg/L to produce the VEGF trap glycoprotein, DOES NOT reasonably provide enablement for a method comprising determining and selecting soy hydrolysate comprising 0.003%-0.027% (w/w) ornithine, and culturing a population of cells expressing any recombinant heterologous glycoprotein in a cell culture medium using said soy hydrolysate with any final concentration of ornithine to produce any recombinant heterologous glycoprotein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in Jn re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention and Breadth of the claims:
Instant claim 1 is directed to a method comprising determining and selecting a soy hydrolysate comprising 0.003%-0.027% (w/w) ornithine, and culturing a population of cells expressing a recombinant heterologous glycoprotein in a cell culture medium comprising said soy hydrolysate to produce the recombinant heterologous glycoprotein. Claim 1 encompasses a genus of recombinant heterologous glycoprotein, which can be produced by various heterologous host cells (such as bacterial, yeast, insect cells or mammalian cells) and comprising different sugar structures such as N-linked, O-linked, or modified glycosylation. Wherein, for instance, the N-linked glycoprotein further comprises various species such as Sialic Acids, G0F, G0 and man5, G1F, G1F-GlcNAc and G2F (see i.e., figure 2 and table 1 of Hamm et al. (Pharmaceuticals 2013, 6, 393-406)). Moreover, claim 1 does not limit the amount of soy hydrolysate used in the culture medium, therefore the final concentration of ornithine in the culture medium can vary from negligible to a high concentration (undefinable depends on the amount of soy hydrolysate added in the culture medium). Therefore the claim is extremely board.
Guidance of the Specification and The Existence of Working Examples:
The disclosure provides working examples regarding using soy hydrolysate comprising with between 0.067 and 0.67 mg ornithine per g (0.0067% - 0.067% (w/w)) soy to produce a trap protein (receptor-Fe fusion protein, VEGF-trap), comprising screening soy hydrolysate to determine the concentration of ornithine (0.067 and 0.67 mg ornithine per g soy, Example 1), and using CHO cells to express VEGF-trap in a culture medium with said soy hydrolysate, wherein the final concentration of ornithine is less than 5.0 mg/L, demonstrating that soy hydrolysate with an ornithine concentration of 2.0 mg/L or less produce higher quality protein product (measured by higher A1 N-glycan levels) and more consistent A1 N-glycan protein production (Example 2). It is noted that the working examples disclose that higher concentration of ornithine (i.e., 6.6 mg/L or 36.6 mg/L ornithine as presented in table 2) is considered not optimal for the claimed method (see parag 000121 and Table 2 of Specification). The disclosure further shows that glycoprotein production and titer is correlated with ornithine in the soy hydrolysate (Example 3 and Example 4). Applicant does not disclose the production of any other species of recombinant heterologous glycoprotein by the claimed method, neither does Applicant use any other different final concentrations of ornithine in the culture medium. Thus Applicant failed to disclose the production of a genus of recombinant heterologous glycoprotein by the claimed method, neither does Applicant disclose using any final concentration of ornithine in the culture medium. In fact, Applicant demonstrates that only ornithine at a concentration less than 5.0 mg/L is selected or optimal for the claimed method (parag 000102, Example 2).
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The state of the prior art with using culture medium comprising ornithine for producing therapeutic proteins (i.e., recombinant heterologous glycoprotein) are summarized by the references of Kang et al. (US 2016/0333385 A1), Oshodi et al. (WO 2014/144198 A1) and Richardson et al. (HUMAN GENE THERAPY, 2016). Specifically, Kang et al. teach a method for manipulating the high mannose glycoform content of recombinant glycoproteins by regulating ornithine metabolism during cell culture (Abstract), demonstrate that the high mannose glycoform content of an expressed recombinant glycoprotein was influenced by ornithine accumulation in the host cell (parag 0043). Kang et al. disclose the correlation of the production of the high mannose glycoform with the concentration of ornithine (see figure 7). Oshodi et al. teach an improved serum-free animal cell culture medium, which can used for the production of a protein of interest. Ornithine, or a combination of ornithine and putrescine can be added to serum-free media or chemically defined media to improve viable cell density, to reduce cell doubling time, and to increase the production of a protein of interest (Abstract). Oshodi et al. teach in some embodiments, the protein of interest is a receptor-Fe-fusion protein, such as an ScFv molecule or a trap molecule. Trap molecules include the VEGF trap and IL-1 Trap proteins (parag 00016). Oshodi et al. teach using ≥ 0.09 mM ± 0.014 mM ornithine (~ 10 mg/L ornithine with the molecular weight of 132 g/mol, parag 0008). Oshodi et al. also teach the use of soy hydrolysate in the culture medium (see Example 1), but do not teach measuring/using ornithine in the soy hydrolysate, as well as the production of A1 N-glycan in the recombinant glycoproteins. Richardson et al. screen different batches of soy hydrolysates for components (productivity markers) that correlated with cell culture performance during the production of two therapeutic antibodies in two CHO cell lines (p523, left column), demonstrate that ornithine and citrulline can accelerate cell growth (p530, left column). These teachings indicate that ornithine has multiple function in cell culture: ornithine is beneficial for cell growth, viability and the increase of the overall production of the expressed protein, ornithine is also capable of promoting specific protein production (i.e., high mannose glycoform in the protein, which is a different N-Glycan commonly exists in a recombinant heterologous glycoprotein) in a concentration-dependent way. Therefore there was no known link between, at least the claimed concentration of ornithine in the soy hydrolysate, and the production of any recombinant heterologous glycoprotein with a higher level of A1 N-glycan as demonstrated in instant disclosure. None of the known effects of the concentration of ornithine in the soy hydrolysate would have been expected to increase the level of A1 N-glycan in a recombinant heterologous glycoprotein.
In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled commensurate with full scope. An artisan of skill would have required undue experimentation to practice the invention with a reasonable expectation of success.
Claims 2, 4-9, 15 and 25-33 depend from, at least, claim 1, and thus inherit the deficiency and are rejected on the same basis.
Related Prior Arts
As stated above, the closest arts Kang et al., Krishnan et al., as well as Richardson et al. do not teach or suggest at least step (b) selecting a soy hydrolysate comprising 0.003% - 0.027% (w/w) ornithine as recited in instant claim 1. One ordinary skill in the art would not be taught or motivated to determine and select a soy hydrolysate comprising 0.003% - 0.027% (w/w) ornithine specifically for the culture of cells expressing a recombinant heterologous glycoprotein. The claimed method is therefore considered novel.
Conclusion
No claims are allowed.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699