DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant’s election of Group I (claims 65-71 and 83-84) in the reply filed on February 11, 2026 is acknowledged. Claims 65-84 are presently pending; claims 72-82 are presently withdrawn.
Objection to the Drawings
3. New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because FIGs. 4-7 and 16-18 are illegible. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
4. 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.
Written Description
5. Claims 65-71 and 83-84 are 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 claims contain 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The claims are directed to methods for producing a recombinant protein comprising adding a “trace element” to a culture media comprising a “host cell.” The claims therefore encompass a myriad of possible trace elements and host cells for producing the recombinant proteins. The claimed method must result in increased expression levels, fermentation yields, or production levels of the recombinant protein as compared to a method without the addition of the trace element (e.g., claims 67, 84), but the specification only demonstrates the trace element cupric sulfate in combination with a yeast host cell as having the required function. The species cupric sulfate is not sufficiently representative of the genus “trace elements” in general; and the species yeast is not sufficiently representative of the genus “host cell.”
A. No Written Description for Producing Fragments of SEQ ID NOs: 1 and 2 (i.e., Claim 66)
The claimed invention recites that the produced recombinant protein may by a recombinant human GM-CSF comprising “an” amino acid sequence having at least about 97% identity with SEQ ID NO: 1 or 2 (i.e., claim 66). The broadest reasonable interpretation for this recitation is: the claim language reads on fragments and variants of GM-CSF. However, the specification only discloses methods of producing a full-length GM-CSFs; it is unknown what fragments of GM-CSF encompassed by the claims may be producible by the claimed invention, and furthermore, which fragments of the GM-CSF retain sufficient functionality to be considered a “GM-CSF.”
The specification discloses production of GM-CSF variant sargramostim (i.e., SEQ ID NO: 2) by the claimed invention at FIG. 3, and provides an analysis of the purity of the produced sargramostim at FIGs. 4-18. Therefore, the specification only discloses production of the GM-CSF sargramostim (i.e., SEQ ID NO: 2).
Since the claims recite the recombinant human GM-CSF comprises “an” amino acid sequence having at least about 97% with SEQ ID NO: 1 or 2, potentially thousands of distinct recombinant “GM-CSF” proteins comprising fragments of the GM-CSF protein domains are encompassed by the claims because: claim 66 reads on any amino acid sequence comprising two or more amino acids that correspond to 97% or greater identity of the homologous region of GM-CSF. However, the specification does not does not define any structural features commonly possessed by members of this genus. The claims recite functional language of the GM-CSF, i.e., that it is a GM-CSF, however a definition by function does not suffice to define the genus because it is only an indication of what the recombinant protein does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the claim-recited genus of recombinant proteins comprising fragments of GM-CSF is highly variable (i.e., each recombinant protein comprising a GM-CSF fragment would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed “GM-CSFs” comprising fragments of the SEQ ID NOs have no correlation between their structure and function.
To address this issue, a brief assessment of the state of the art regarding fragments of bioactive amino acid sequences is made herein. Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teaches regarding fragments of bradykinin: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B 2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was surprising and not predictable that the fragments of bradykinin had substantially altered and different biological activity compared to the full-length bradykinin.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teaches regarding a fragment of the RGDF peptide that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the tetrapeptide showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of fragmenting an amino acid sequence resulting in substantially altered and different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting an amino acid sequence resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible fragments of SEQ ID NOs: 1 and 2 as instantly claimed, and therefore what species of the claim-recited genus are “GM-CSF.” Therefore, neither the art nor the specification provides a sufficient representative number of recombinant proteins comprising fragments of GM-CSF that retain sufficient biological activity when compared full-length GM-CSF to meet the written description requirement for instant claim 66 directed “wherein the recombinant protein is recombinant human granulocyte macrophage-colony stimulating factor (rhu GM-CSF) protein, comprising an amino acid sequence having at least about 97% identity with SEQ ID NO:1 or SEQ ID NO: 2.”
It is therefore unknown what members of the claim-recited “GM-CSF” genus retain sufficient biological activity to be considered a GM-CSF, nor which members of the genus the claimed invention can produce; Applicant has not shown possession of a representative number of species that have the claimed functions. The specification therefore provides insufficient written description to support the genus of GM-CSF fragments and variants of SEQ ID NOs: 1 and 2 encompassed by claim 66. Given all of the above, Applicant does not have adequate written description for fragments and variants of SEQ ID NOs 1 and 2.
B. No Written Description for the Breadth of the Claims: “Host Cells” and “Trace Elements”
Applicant has provided adequate written description for: methods of producing recombinant protein by adding copper to a culture medium comprising yeast capable of producing the recombinant protein during fermentation. However, the claims are far broader and encompass: methods of producing recombinant protein by adding any trace element to a culture medium comprising any host cell capable of producing the recombinant protein during fermentation.
The claimed invention recites “trace elements” and “host cells” in general, and the broadest reasonable interpretation for this recitation is: the claim language reads on any trace element used in combination with any host cell, including the 16 mammalian cells recited in the specification at para. [0081]. However, the specification only provides support for a decidedly narrower invention specifically utilizing copper and yeast, as set below.
The specification discloses dissolved oxygen profiles and culture biomass for yeast cultured with six trace elements, including cupric sulfate (i.e., Examples 1-2); and comparisons of GM-CSF titers, glycoforms, and purity obtained with and without the copper supplementation (i.e., Examples 3-8). No “host cell” other than yeast is demonstrated in the specification, nor is a beneficial effect of any “trace element” other than cupric sulfate demonstrated in the specification. More specifically, none of molybdate, zinc, iron, boron, or manganese is shown to have any effect of dissolved oxygen or biomass in yeast—only copper is shown to have the beneficial effect (see specification at FIGs. 1A and 2A).
The claimed method must possess specific functions, such as producing a recombinant protein; and increasing expression levels, fermentation yields, or production levels of the recombinant protein as compared to a method without the addition of the trace element (e.g., claims 67, 84). However, the specification does not define any structural features commonly possessed by members of the genus “host cell” or “trace element.” Functional language specifying what the “host cell” and “trace element” does not suffice to define the genus because it is only an indication of what the “host cell” and “trace element” does rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. Thus, the encompassed “host cells” and “trace elements” have no correlation between structure and function. To address this issue, a brief assessment of the state of the art of using “host cells” and “trace elements” to produce recombinant proteins is made herein.
Gibco (“peptones supplements feeds technical reference guide” (2019)) is directed to considerations for selecting media components to enhance performance in mammalian and microbial cell culture fermentation applications. Gibco at introduction. Gibco teaches that successful media design requires understanding key media drivers for the host cell being used, and individual experimentation with a variety of peptones (which comprises the trace element source) is recommended to select the optimum peptone or combination of peptones. Gibco at fermentation applications. Gibco shows that the growth profiles of yeast and bacteria using different peptones; S. cerevisiae yeast grew well with peptones (2, 3, 4) but not (1), whereas E. faecalis bacteria grew well with peptones (1, 3) but not (2, 4). Id. at FIGs. 1-2. This demonstrates different of species of “host cells” respond unpredictably to media comprising different formulations and trace elements. Regarding mammalian cells, Gibco teaches that there is substantial variability in how even different lines of the same cell type, e.g., CHO cells, will respond to media formulations comprising trace elements; CHO cell line #3 produced markedly higher protein titers with peptones (1, 4) compared to CHO cell lines #1-2, whereas there was no difference in protein titer between the cell lines with peptones (2, 4). Gibco at cell culture applications FIG. 6. This highlights the high degree of unpredictability inherent to matching a “host cell” to a “trace element” to produce a recombinant protein, and thus the need for individual experimentation.
Zhang et al. ("Comparative genomics of trace elements: emerging dynamic view of trace element utilization and function." Chemical reviews 109.10 (2009): 4828-4861) is directed to a comparative study of trace metal utilization. Zhang et al. at title. Zhange et al. teaches that about 30% of eurkaryotic species, and about 25% of bacteria, do not utilize molybdenum. Zhang et al. at FIG. 4A. Zhang et al. teaches there is high variability in the percentage of eukaryotic and bacterial species that utilize cobalt and/or nickel. Zhang et al. at FIG. 7A. Zhang et al. teaches about 5% of eukaryotic species, and about 20% of bacteria, do not utilize copper. Zhang et al. at FIG. 9A. Therefore, the genus “host cell” clearly encompasses species that cannot utilize species of the genus “trace element” to increase the production of a protein, let alone using copper to increase the production of a protein.
Gazaille et al. (www.bioprocessintl.com/cell-line-development/the-medium-is-the-message-considering-the-effects-of-trace-metals-on-cell-culture-performance, published September 1, 2024) summarizes the state of the art well: “Metals play a significant role in culture performance. In one way or another, trace metals strongly influence cell growth, productivity, glycosylation patterns, charge profiles, and energy metabolism—just to name a few parameters from a comprehensive list. As far as culture processes, all trace metals have a similar story: They bring both benefits and limitations depending on what concentrations are supplied and what cell lines are applied.” Gazaille et al. at what role do trace metals and related components play in cell culture. Furthermore, Gazaille et al. highlights that “development scientists still have much to discover about optimizing cell culture,” and that beyond selecting a cell line, development scientists should still “experiment with different culture-media compositions and supplementation strategies to control levels of cell growth, protein expression, and metabolite buildup.” Gazaille et al. at introduction. In other words, the state of the art indicates that significant experimentation is required to properly match a “host cell” to a “trace element” to increase or optimize a recombinant protein’s expression / yield.
Neither the art nor the specification provides a sufficient representative number of “host cell” or “trace element” species that increase the production of a recombinant protein in culture to meet the written description requirement for instant claims directed to methods for producing recombinant proteins comprising genus “host cell” and “trace element.” It is unknown what “host cells” may be paired with what “trace elements”—other than yeast with copper, as demonstrated by the instant specification—to effect an increase in production of a recombinant protein. Applicant has not shown possession of a representative number of species that have the claimed function(s). Given all the above, Applicant does not have possession for am method of producing a recombinant protein comprising “host cells” and “trace elements.”
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
6. Claims 65-71 and 83-84 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of producing a protein comprising adding a copper salt, e.g., cupric sulfate, to a culture media comprising yeast, does not reasonably provide enablement for a method of producing a protein comprising adding a “trace element” to a culture media comprising a “host cell.” 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.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention:
The claims are drawn to methods of producing a recombinant protein comprising adding a “trace element” to culture medium comprising a “host cell” comprising nucleotides encoding the recombinant protein. The dependent claims recite specific recombinant proteins, a trace element, concentrations of the trace element, and function(s) of the trace element.
(2) The breadth of the claims:
The claims are broad and encompass myriad “host cells” and “trace elements.” The specification indicates host cell may include at least 16 types of mammalian cells at para. [0081].
(5) The predictability or unpredictability of the art:
The state of the art indicates there is substantial unpredictability associated with matching “host cells” to “trace elements” to improve recombinant protein production in vitro. In particular, Gibco is directed to considerations for selecting media components to enhance performance in mammalian and microbial cell culture fermentation applications. Gibco at introduction. Gibco teaches that successful media design requires understanding key media drivers for the host cell being used, and individual experimentation with a variety of peptones (which comprises the trace element source) is recommended to select the optimum peptone or combination of peptones. Gibco at fermentation applications. Gibco shows that the growth profiles of yeast and bacteria using different peptones; S. cerevisiae yeast grew well with peptones (2, 3, 4) but not (1), whereas E. faecalis bacteria grew well with peptones (1, 3) but not (2, 4). Id. at FIGs. 1-2. This demonstrates different of species of “host cells” respond unpredictably to media comprising different formulations and trace elements. Regarding mammalian cells, Gibco teaches that there is substantial variability in how even different lines of the same cell type, e.g., CHO cells, will respond to media formulations comprising trace elements; CHO cell line #3 produced markedly higher protein titers with peptones (1, 4) compared to CHO cell lines #1-2, whereas there was no difference in protein titer between the cell lines with peptones (2, 4). Gibco at cell culture applications FIG. 6. This highlights the high degree of unpredictability inherent to matching a “host cell” to a “trace element” to produce a recombinant protein, and thus the need for individual experimentation.
Zhang et al. is directed to a comparative study of trace metal utilization. Zhang et al. at title. Zhange et al. teaches that about 30% of eurkaryotic species, and about 25% of bacteria, do not utilize molybdenum. Zhang et al. at FIG. 4A. Zhang et al. teaches there is high variability in the percentage of eukaryotic and bacterial species that utilize cobalt and.or nickel. Zhang et al. at FIG. 7A. Zhang et al. teaches about 5% of eukaryotic species, and about 20% of bacteria, do not utilize copper. Zhang et al. at FIG. 9A. Therefore, the genus “host cell” clearly encompasses species that cannot utilize species of the genus “trace element” to increase the production of a protein, let alone using copper to increase the production of a protein.
Gazaille et al. summarizes the state of the art well: “Metals play a significant role in culture performance. In one way or another, trace metals strongly influence cell growth, productivity, glycosylation patterns, charge profiles, and energy metabolism—just to name a few parameters from a comprehensive list. As far as culture processes, all trace metals have a similar story: They bring both benefits and limitations depending on what concentrations are supplied and what cell lines are applied.” Gazaille et al. at what role do trace metals and related components play in cell culture. Furthermore, Gazaille et al. highlights that “development scientists still have much to discover about optimizing cell culture,” and that beyond selecting a cell line, development scientists should still “experiment with different culture-media compositions and supplementation strategies to control levels of cell growth, protein expression, and metabolite buildup.” Gazaille et al. at introduction. In other words, the state of the art indicates that significant experimentation is required to properly match a “host cell” to a “trace element” to increase or optimize a recombinant protein’s expression / yield.
A person of skill in the art would readily appreciate that significant unpredictability exists around how to match a “host cell” with a “trace element” (including the amount of the trace element) for the in vitro production of recombinant proteins. The lack of significant guidance from the instant specification or prior art with regard to matching trace elements, concentration, and host cells makes practicing the claimed invention highly unpredictable.
6) the amount of direction or guidance provided by the inventor:
The instant specification provides dissolved oxygen profiles and culture biomass for yeast cultured with six trace elements, including cupric sulfate (i.e., Examples 1-2); and comparisons of GM-CSF titers, glycoforms, and purity obtained with and without the copper supplementation (i.e., Examples 3-8). No “host cell” other than yeast is demonstrated in the specification, nor is a beneficial effect of any “trace element” other than cupric sulfate demonstrated in the specification. More specifically, none of molybdate, zinc, iron, boron, or manganese is shown to have any effect of dissolved oxygen or biomass in yeast—only copper is shown to have the beneficial effect (see specification at FIGs. 1A and 2A)
Given the evidence above and lack of known correlation between trace element: copper to other trace elements for producing recombinant protein, let alone in all the cell types encompassed by the term “host cell,” one of skill in the art could not reasonably extrapolate the instant findings regarding beneficial effects of copper supplementation on recombinant protein production in yeast to genus “host cell” and “trace element,” without undue experimentation.
In conclusion, the claimed invention does not provide enablement for method of producing recombinant protein comprising “host cells” and “trace elements.” Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
7. 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 65-71 and 83-84, are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims either directly recite or depend from claims that recite a host cell “comprising a nucleic acid molecule encoding the recombinant protein and being capable of producing the recombinant protein during fermentation.” The term “being capable of” renders the claims indefinite because it is unclear whether the limitation(s) following the phrase “nucleic acid molecule encoding the recombinant protein” are part of the claimed invention. See MPEP 2173.05(d). Appropriate clarification or correction is required.
Claim Rejections - 35 USC § 102
8. 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Additionally, it should be noted that normally only one reference should be used in making a rejection under 35 U.S.C. 102. However, MPEP § 2131.01(III) instructs that a 35 U.S.C. 102 rejection using additional references has been held to be proper when the additional reference is used to: (a) prove the primary reference contains an "enabled disclosure”; (b) explain the meaning of a term used in the primary reference; or (c) show that a characteristic not disclosed in the reference is inherent.
Claims 65-71 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Bhatacharya et al. ("Production and purification of recombinant human granulocyte–macrophage colony stimulating factor (GM-CSF) from high cell density cultures of Pichia pastoris." Bioprocess and biosystems engineering 30.5 (2007): 305-312), in light of Giorgio et al. ("Preparation of a copper-deficient medium for yeast growth." Journal of Bacteriology 86.5 (1963): 1037-1040).
Claim 65 is drawn to a method for production of a recombinant protein, comprising (a) adding a trace element to a culture medium comprising a host cell, the host cell comprising a nucleic acid molecule encoding the recombinant protein and being capable of producing the recombinant protein during fermentation, and (b) isolating the recombinant protein, wherein the trace element is exogenously added to the culture medium to supplement an amount of trace element in the culture medium.
Claim 66 is drawn to the method according to claim 65, wherein the recombinant protein is recombinant human granulocyte macrophage-colony stimulating factor (rhu GM-CSF) protein, comprising an amino acid sequence having at least about 97% identity with SEQ ID NO:1 or SEQ ID NO: 2.
Claim 67 is drawn to the method according to claim 65, wherein the addition of the trace element during production of the recombinant protein increases the expression levels, the fermentation yield, and/or the production levels of the recombinant protein, as compared to a method without the addition of the trace element.
Claim 68 is drawn to the method according to claim 65, wherein the trace element is copper, or a form of a copper derivative, copper compound, and/or copper salt.
Claim 69 is drawn to the method of claim 68, wherein the copper salt is cupric or copper sulfate.
Claim 70 is drawn to the method of claim 68, wherein the copper trace element is added to the culture medium in an amount of about 0.5 µM to about 100 µM, about 0.5 µM to about 80 µM, or about 1 µM to about 20 µM.
Claim 71 is drawn to the method of claim 65, wherein the nucleic acid molecule is a vector and/or has a codon- optimized sequence.
Bhatacharya et al. is directed to the production and purification of a recombinant protein, i.e., GM-CSF, from cultures of a host cell, i.e., Pichia pastoris yeast. Bhatacharya et al. at title. Bhatacharya et al. dilutes 200X PTM1 salts comprising 3.0 g/L cupric sulfate–5H2O, e.g., a “trace element,” into a basal salt medium to create batch medium, e.g., “culture mediums.” Bhatacharya et al. at page 307, right col. Bhatacharya et al. therefore adds about 60 µM cupric sulfate,1 i.e., a copper salt, to the culture medium. The host cell comprises plasmid/vector pPIC9K-GMCSF, e.g., “a nucleic acid capable of producing the recombinant protein during fermentation.” Bhatacharya et al. at page 306, right col. Bhatacharya et al. cultures the host cell comprising nucleic acid for expressing recombinant protein in culture medium having added trace element and then “isolates” the recombinant protein, i.e., GM-CSF, from the culture medium by centrifugation. Bhatacharya et al. at page 308, left col. The 5 mL aliquot of PTM1 salts “exogenously” added to basal salt medium to create batch medium “supplements” any amount of trace elements present in the basal salt medium. Bhatacharya et al. at page 307, right col. (claims 65, 68-71)
Bhatacharya et al. discloses the GM-CSF plasmid/vector was constructed using human GM-CSF cDNA to express the 127 AA GM-CSF. Bhatacharya et al. at page 306, right col.; introduction. Although Bhatacharya et al. does explicitly show the sequence of the human GM-CSF, instantly-claimed SEQ ID NO: 1 is 100% identical to the known human GM-CSF sequence (claim 66). An alignment of SEQ ID NO: 1 to reference human GM-CSF sequence, shown only to evidence that the instantly claimed SEQ ID NO: 1 is identical to human GM-CSF, is provided below for Applicant’s convenience:
RESULT 1
AAE13117
(NOTE: this sequence has 184 duplicates in the database searched.
See complete list at the end of this report)
ID AAE13117 standard; protein; 127 AA.
XX
AC AAE13117;
XX
DT 15-JUN-2007 (revised)
DT 28-JAN-2002 (first entry)
XX
DE Mature human GM-CSF protein.
XX
KW Immunostimulatory fusion protein; IFP; antigen component; therapy;
KW immunostimulatory component; T-cell mediated immune response; DC;
KW dendritic cell; colon cancer; breast carcinoma; ovarian cancer;
KW HER-2 protein; granulocyte-macrophage colony stimulating factor; GM-CSF;
KW human.
XX
OS Homo sapiens.
XX
FH Key Location/Qualifiers
FT Misc-difference 100
FT /note= "Encoded by ACT"
XX
CC PN WO200174855-A2.
XX
CC PD 11-OCT-2001.
XX
CC PF 30-MAR-2001; 2001WO-US010515.
XX
PR 30-MAR-2000; 2000US-0193504P.
XX
CC PA (DEND-) DENDREON CORP.
XX
CC PI Laus R, Vidovic D, Graddis T;
XX
DR WPI; 2001-662965/76.
DR N-PSDB; AAD21569.
DR PC:NCBI; gi442762.
XX
CC PT An immunostimulatory fusion protein comprising the intracellular domain
CC PT of HER-2 and an antigen elicits an immune response to the antigen and is
CC PT useful for the treatment of associated cancer associated.
XX
CC PS Example 3; Page 30; 59pp; English.
XX
CC The invention relates to immunostimulatory fusion proteins (IFP) and
CC nucleic acid molecules encoding such proteins. The IFPs comprise a
CC polypeptide antigen component and an immunostimulatory component derived
CC from the intracellular domain of HER-2 protein which is effective to
CC elicit a protective dendritic cell (DC)-induced T-cell mediated cellular
CC immune response to the antigen. IFP or superactivated dendritic cells are
CC used to treat cancer e.g. breast carcinoma, ovarian and colon cancer
CC associated with a particularly antigen. The present sequence is a mature
CC human granulocyte-macrophage colony stimulating factor (GM-CSF). This
CC sequence is used in the HER500-hGM-CSF fusion constructs of the invention
CC
CC Revised record issued on 15-JUN-2007 : Enhanced with precomputed
CC information from BOND.
XX
SQ Sequence 127 AA;
Query Match 100.0%; Score 673; Length 127;
Best Local Similarity 100.0%;
Matches 127; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLE 60
Qy 61 LYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFD 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFD 120
Qy 121 CWEPVQE 127
|||||||
Db 121 CWEPVQE 127
Bhatacharya et al. in light of Giorgio et al. inherently discloses “wherein the addition of the trace element during production of the recombinant protein increases the expression levels, the fermentation yield, and/or the production levels of the recombinant protein, as compared to a method without the addition of the trace element,” i.e., claim 67. As noted above, Bhatacharya et al. discloses addition of a copper “trace element” to the culture media. Bhatacharya et al. also discloses the importance of sustained yeast growth, “which helps in the efficient expression of the recombinant protein,” i.e., fermentation yield. Bhatacharya et al. at page 309, left col. However, Bhatacharya et al. does not explicitly disclose why the copper “trace element” was added to the media.
Giorgio et al. is directed to copper-deficient yeast growth medium preparations. Giorgio et al. at title. Giorgio et al. discloses that yeast growth is significantly impaired in copper-deficient media, and that yeast growth is restored by adding back the copper. Giorgio et al. at abstract. Giorgio et al. defines why Bhatacharya et al. added the copper: to support the growth and fermentation yield of the yeast as compared to not having the additional copper. Bhatacharya et al. in light of Giorgio et al. therefore inherently teaches that not adding copper will result in reduced fermentation yield by the yeast, however the addition of copper increases fermentation yield by the yeast, which reads on the limitations: “wherein the addition of the trace element during production of the recombinant protein increases the expression levels, the fermentation yield, and/or the production levels of the recombinant protein, as compared to a method without the addition of the trace element” of claim 67. Therefore, claim 67 is inherently anticipated by Bhatacharya et al. in view of Giorgio et al. (claim 67).
Accordingly, Bhatacharya et al. anticipates instant claims 65-71.
Conclusion
9. No claim is allowed.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
1 The molar mass of CuSO4 pentahydrate is 249.69 g/mol. Therefore, the pre-diluted concentration of 3.0 g/L divided by the molar mass of 249.69 g/mol results in an equivalent molar concentration of 12,015 µM; once diluted 1:200, the resultant molar concentration is about 60 µM CuSO4 in the culture media.
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