Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1, 3, 10-21, and 24 are currently pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-10 and 21-24, in the reply filed on Jan. 1, 2025 is acknowledged. Claims 11-20 are withdrawn for being drawn to non-elected subject matter, and claims 1, 3, 10, 21, and 24 have been considered on the merits. All arguments were fully considered.
Benefit of Priority Claim
Acknowledgement is made of applicant’s claim for the benefit of the prior-filed application US 62/828,867 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c). The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Entitlement to priority to April 3, 2019 does not apply to the subject matter of claims 1, 3, 10, 21, and 24 (e.g., due to a lack of support for “0.1 mg to 1 mg per 100 ml” or “0.1 mg to 10 mg per 100 ml”), therefore the earliest effective filing date of claims 1, 3, 10, 21, and 24 is April 3, 2020 based on the filing date of PCT/US2020/026598.
Previous Rejections
Status of the rejections: the previous claim rejections under sections 112(b) and 102 are withdrawn in view of applicant’s claim amendments.
Claim Objections
Claims 1 and 3 are objected to because of the following informalities:
In claim 1, it would be clearer to either introduce the abbreviation “TPO” at the first occurrence of thrombopoietin in the entire claim set or completely remove “(TPO)” from claims 17 and 21. Appropriate correction is requested.
In claim 3, the term transforming growth factor beta (TGF-b) is redundantly repeated within a single list. Appropriate correction is requested.
Claim Interpretation
In the claims, the preamble phrase “cryopreservation medium” is interpreted to encompass any medium suitable for use as a preservation medium by a person skilled in the art and expressly limited to comprising at least one component capable of protecting a cell or tissue in the medium from injury during freezing and/or thawing (see instant specification at pg. 7, lines 17-26), such as a cryoprotective or cryopreservative chemical or composition (pg. 25, lines 6-21). The instant application defines a medium as one used to grow, culture and maintain organs, tissues, or cells in vitro (pg. 5, lines 8-9) and furthermore, a cryopreservative composition as one that reduces injury during freezing and thawing to cells and tissues (pg. 7, lines 17-24). For example, a cryopreservation medium includes cryopreservative media known in the prior art (pg. 18, lines 14-17). Thus, claims 1 and 21 are both interpreted with an implied limitation to wherein the medium is permissive for cell viability in vitro, e.g., regarding water content, isotonicity/osmolality, pH, electrolyte balance, and/or mineral content, depending if the biological sample comprises a living cell, tissue or organ. However beyond the above implied limitations, the claimed medium products are not interpreted to have any additional implied limitation.
In the claims, the phrase “the one or more modified type 1 cytokines have similar biological activity as the one or more naturally occurring type 1 cytokines” is interpreted under a broadest reasonable standard as requiring the “modified type 1 cytokine” to retain all biological activities of at least one naturally occurring type 1 cytokine to which it has at least 90% sequence homology, such as wherein the activity is at least at a minimum level detectable by at least one assay. As the “modified type 1 cytokine” is defined in the claims, the cytokine does not encompass any form having similar biological activity nor any compound that can be modified or metabolized in a cell culture medium or intracellularly to provide a similar biological activity form as described at instant pg. 29, lines 6-12.
Claim Rejections - 35 USC § 112(a), New Matter
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, 3, 10, 21, and 24 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 claim 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. The low dose in claim 1 or 21 comprising “0.1 mg to 1 mg per 100 ml” or “0.1 mg to 10 mg per 100 ml” lacks support in the application as filed and thus constitutes new matter.
37 CFR 1.118(a) states “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”. In the instant case, the recitation of the limitation “0.1 mg to 1 mg per 100 ml” (claim 1) or “0.1 mg to 10 mg per 100 ml” days” (claim 21) is considered new matter. Upon review of the instant specification, examiner could not find explicit or implicit support for this limitation (see e.g., instant pg. 2, lines 23-27; pg. 11, lines 26-31; original claims 8-9; US 62/828,867 at pg. 2, lines 16-20, claims 8-9 and 17-18). Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of a cryopreservation medium comprising these specific concentration ranges of modified type 1 cytokine(s).
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981) teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed…If a claim is amended to include subject matter, limitation or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes, “When an amendment is filed in reply to an objection or rejection based on U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendment made to the disclosure”. This is a new matter rejection.
Claim Rejections - 35 USC § 112(a), Written Description (new)
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, 3, 10, 21, and 24 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 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.
When claim 1 is analyzed in light of the specification, the instant invention is directed to a medium comprising at least one modified type 1 cytokine comprising at least 90% homology with the amino acid sequence of at least one naturally occurring type 1 cytokine, wherein the cytokine is limited to the group consisting of IL-2, IL-12, IL-18, IL-27, interferon-gamma (IFNg), leukemia inhibiting factor (LIF), ciliary neurotrophic factor (CNTF), thrombopoietin, tumor necrosis factor alpha (TNFa), tumor necrosis factor b (TNFb), and prolactin; and wherein the modified type 1 cytokine has a similar biological activity as such a naturally occurring homolog.
M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.”
In the instant case, claims 1, 3, and 10 each broadly comprises a genus of modified type 1 cytokines defined as comprising at least 90% homology with the amino acid sequence of at least one naturally occurring IL-2, IL-12, IL-18, IL-27, interferon-gamma (IFNg), leukemia inhibiting factor (LIF), ciliary neurotrophic factor (CNTF), thrombopoietin, tumor necrosis factor alpha (TNFa), tumor necrosis factor b (TNFb), and prolactin, but required to have similar biological activity to said naturally occurring homolog.
Relatedly, claims 21 and 24 each broadly comprises a modified type 1 cytokine genus defined as comprising at least 90% homology with the amino acid sequence of at least one naturally occurring granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), erythropoietin (EPO), thrombopoietin (TPO), stem cell factor (SCF), stem cell growth factor (SCGF), and bone morphogenetic protein (BMP), wherein the modified cytokine has similar biological activity to said naturally occurring homolog.
As these naturally occurring cytokine proteins exist throughout Vertebrata species (such as in fish, amphibians, and birds), and in some cases in invertebrates (see e.g., the BMP transforming growth factor beta (Gelbart, Development 107 Suppl:65-74 (1989) at Abstract; Boulay et al., Immunity 19: 159-63 (2003) at Fig. 1), the scope is vast and diverse for any such modified cytokines within at least 90% sequence homology of any naturally occurring member. Then among these sequence variants, the actual genus of the claims is limited to only those functionally defined as have similar biological activity. However many of these cytokines identifiable by sequence homology have never been assayed for any biological function and may lack an experimental setup to determine similarity of all their biological functions. Moreover, some of these cytokines (e.g., IFNg, TNFa, thrombopoietin, and prolactin) have numerous different biological activities (e.g., cell differentiation, stem cell renewal, and/or hormonal), each activity of which needs to remain similar for any modified variant encompassed by the claims according to the phrase “have similar biological activity.”
The instant specification is silent as to any sequence of a single modified cytokine encompassed by these claims (e.g., having a mutation, insertion, and/or deletion). The written description does provide non-sequence based modified cytokine examples of: fusokines like IL-2 fused with IL-12, IL-2 fused with IL-18, IL-18 fused with EGF, GM-CSF fused to IL-2 (GIFT2), IL-3, IL-15 (GIFT15), IL-21 (GIFT21) or an N-terminally truncated CCL2 (GMME1), as well as pegylated interferons that are not IFNg (pg. 45, lines 21-34, pg. 46, lines 11-12, pg. 47, lines 24-30). Thus, the only representative species of claim 1 described are species related to modified IL-2, IL-12, and IL-18, and the only representative species of claim 21 are modified GM-CSF.
Furthermore, the instant specification lacks any working example of a cryopreservation medium comprising a “modified” cytokine or how to determine similarity of biological activity to a naturally occurring cytokine, such as using an assay quantitatively determining receptor binding or signaling, cell differentiation or proliferation effects, stimulating/suppressing release of another cytokine, activating or inhibiting an immune activity (e.g., inflammation), cytotoxicity, endocrine activity, immunoprotective or immunopathogenic activity, regulation and/or modulation of a specific type of immune cell or inflammatory response (see e.g., instant Table 1).
Thus, there is a lack of evidence in the instant specification as filed that the inventors were in possession of a cryopreservation medium comprising the full scope of the genus of any modified type 1 cytokine having at least 90% sequence homology and similar biological activity with a natural occurring type 1 cytokine as recited in the claims.
Regarding claim 10, the required concentration of the modified cytokine is further limited as being within one hundred to 1 billion International Units per mL while stilling satisfying the limitation of being within 0.1-1 mg per 100 mL. Similarly for claim 24, the required concentration of the modified cytokine is further limited as being within one hundred to 1 billion International Units per mL while stilling satisfying the limitation of being within 0.1-10 mg per 100 mL. However the prior art is silent as to how to determine International Unit activities over the scope of modified type 1 cytokines defined as comprising at least 90% homology with the amino acid sequence of at least one naturally occurring (1) IL-2, IL-12, IL-18, IL-27, IFNg, LIF, CNTF, TPO, TNFa, TNFb, and prolactin, or (2) GM-CSF, G-CSF, M-CSF, EPO, TPO, SCF, SCGF, and BMP; wherein the modified cytokine has similar biological activity to said naturally occurring homolog. Furthermore, the instant application lacks any working example of comparing a “modified” cytokine activity to a naturally occurring cytokine activity, such by describing a biological assay or pointing to techniques known in the prior art.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide any description of a modified cytokine within the scope of the genus recited in the claim. Thus, the skilled artisan cannot envision how to identify which modified cytokines have similar biological activity for any cytokine of the groups of cytokines recited. Critically, the specification fails to describe enough representative structures as well as any assay to determine the requisite functionality or any structural feature having sufficient nexus to the functionally defined genus, such as a specific type of mutation or sequence variation.
Therefore, the skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the entire scope of claim 1 or 21.
35 USC § 112(a), Enablement (new)
Claims 1, 3, 10, 21, and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to produce a medium composition reasonably expected to provide a cryopreservation function comprising the modified type 1 cytokine(s) recited in claim 1 or 21.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of the claims:
The claims are directed to a composition comprising any type 1 cytokine having at least 90% sequence homology with any naturally occurring IL-2, IL-12, IL-18, IL-27, interferon-gamma (IFNg), leukemia inhibiting factor (LIF), ciliary neurotrophic factor (CNTF), thrombopoietin, tumor necrosis factor alpha (TNFa), tumor necrosis factor b (TNFb), and prolactin; or any granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), erythropoietin (EPO), thrombopoietin (TPO), stem cell factor (SCF), stem cell growth factor (SCGF), and bone morphogenetic protein (BMP) so long as this cytokine has similar biological activity to at least one such naturally occurring homolog.
The state of the art:
The prior art teaches living cell cryopreservation methods using media comprising low doses of unmodified cytokines (e.g., TPO), modified cytokines like IL-2, GM-CSF and EPO, as well as cytokine/growth factor variants generally having the activity of naturally occurring forms (see e.g., Bessette (WO2020014245A1) at abstract, [0099], [0004]; Bernstein (US20090022696A1) at [0255] and [0160]; and Fong (US 2013/0004648A1) at [0018], [0021], [0073], [0114]). The prior art also teaches sequence variants of IL-2, GM-CSF, and EPO having at least 99% sequence identity to a natural form but which do not have similar bioactivity in all respects, such as IL-2-N88D (or IgG-(IL-2N88D)2) with altered binding to one receptor (IL-2Rβγ) but not another (IL-2Rαβγ) or EPO-S104I having a complete loss of activity on one cell type (Peterson et al., J Autoimmun 95: 1-14 (2018) at pg. 2, right col., last para.; Gan et al., Stroke 43: 3071-7 (2012) at Fig. 1, pg. 3, last para., to pg. 4, 1st para.).
Additionally, the prior art teaches routine techniques (e.g., cell-based bioassays for cell proliferation) for quantifying the potency of any cytokine regarding one or more of its biological activities; however these are based primarily on primate and murine systems and unpredictability arises due to variability introduced by cytokine production, post-translational modifications, excipients present, and storage conditions (Meager, Methods 38: 237-52 (2006) at Abstract, pg. 241, right col., last para., to pg. 242, left col., 2nd para.; pg. 243, left col., last para., to pg. 244, left col., 1st para.; Table 2).
The prior art does not teach a cryopreservation medium comprising a cytokine protein that is less than 95% identical to its closest natural homolog or wherein every biological activity is determined to be similar to such homolog. Thus, these aspects over the scope of the entire genus of cytokines recited in claim 1 or 21 must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue burden being on such an artisan.
The amount of direction and guidance and working examples provided by Applicant:
The instant specification provides no direction, guidance or working examples for determining a similarity of biological activity for two or more cytokines. As a cytokine can have multiple activities, including diverse activities so as to be considered pleiotropic, the modified type 1 cytokines encompassed by the invention must be known or shown to have similar activity over all biological activities, such as using an assay(s) determining the activity of receptor binding or signaling, effect on a cell type (e.g., Th1, Th2, macrophage, hematopoietic, tumor, leukocytes, neutrophil, or B cells), including cell differentiation or proliferation effects, stimulating/suppressing release of another cytokine, activating or inhibiting an immune activity (e.g., inflammation), cytotoxicity, isotype switching, inhibiting viral replication, stimulating antibody secretion, endocrine activity, immunoprotective or immunopathogenic activity, regulation and/or modulation of a specific immune response (see e.g., instant Table 1). Further, undue and unreasonable experimentation would be required in some instances to develop biological activity assays (e.g., cell-based assays) to compare the biological activities of modified cytokines to their naturally occurring homologs, such as for not well studied species of invertebrates, fish, amphibians, or birds.
Thus, there is no evidence in the instant application or the prior art that the scope of modified cytokines encompassed by the claims could predictably provide a cryopreservation function and extensive experimentation would be required to determine which modified cytokines fit the definition recited over the scope of possible cytokines and modifications thereof.
In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art to which it pertains or with which it is most nearly connected to make/use the genus of modified cytokines having at least 90% sequence homology with (1) at least one naturally occurring IL-2, IL-12, IL-18, IL-27, IFNg, LIF, CNTF, TPO, TNFa, TNFb, or prolactin, and where the modified cytokine has similar biological activity to this natural homolog; or alternatively with (2) at least one naturally occurring GM-CSF, G-CSF, M-CSF, EPO, SCF, SCGF, and BMP, and wherein the modified cytokine has similar biological activity to at least one such naturally occurring homolog. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims, undue and/or unreasonable experimentation would have been required for one skilled in the art to produce the recited product over the full scope of the claims.
Claim Rejections - 35 USC § 112(b) (new)
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 1, 3, 10, 21, and 24 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 pre-AIA the applicant regards as the invention.
Claim 1 recites the term “modified type 1 cytokine” comprising a modified amino acid sequence defined in relation to a natural (unmodified) type I cytokine “selected from the group of interleukins consisting of IL-2, IL-12, IL-18, IL-27, interferon-gamma (IFNg), leukemia inhibiting factor (LIF), ciliary neurotrophic factor (CNTF), thrombopoietin, tumor necrosis factor alpha (TNFa), tumor necrosis factor b (TNFb), and prolactin.” However IFNg is not categorized as a type I cytokine, instead conventionally categorized as a type II cytokine (Schwartz et al., Nat Rev Rheumatol 12: 25-36 (2016) at pg. 3, last two para.). Thusly, a person skilled in the art would not understand the metes and bounds of a modified type 1 cytokine comprising 90% sequence homology to an IFNg. Claims 3, and 10 are included in this rejection for being dependent on indefinite claim 1.
In each of claims 1 and 21, the term “similar” regarding a biological activity is a relative term which renders the claim indefinite because neither the claim nor the specification provides a standard for ascertaining a requisite minimum degree of similarity and, thus, one of ordinary skill in the art would not be reasonably appraised of the scope of these claim limitations. Claims 3, 10, and 24 are included in this rejection for being dependent on an indefinite claim.
Claim 21 recites the term “modified type 1 cytokine” comprising a modified amino acid sequence defined in relation to a natural (unmodified) type I cytokine “selected from the group of interleukins consisting of granulocyte macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M- CSF), erythropoietin (EPO), thrombopoietin (TPO), stem cell factor (SCF), stem cell growth factor (SCGF), and bone morphogenetic protein (BMP).” However none of M-CSF, SCF, SCGF, and BMP are categorized as a type I cytokine (see e.g., Schwartz et al., Nat Rev Rheumatol 12: 25-36 (2016) at pg. 2, last para., to pg. 3, 4th para.). Thusly, a person skilled in the art would not understand the metes and bounds of a modified type 1 cytokine comprising 90% sequence homology to an M-CSF, SCF, SCGF, or BMP. Claim 24 is included in this rejection for being dependent on indefinite claim 21.
Claim Rejections - 35 USC § 103 (new)
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Fong (US 2013/0004648A1; IDS ref.) in view of Zhao (Zhao et al., Stem Cells 12: 339-47 (1994)).
The claims are interpreted as set forth in a previous section.
Regarding claim 1, Fong teaches a medium (cell culture expansion medium) comprising a modified type I cytokine IL-2 (IL-2-IL-6) ([0113]-[0114]; [0068]) wherein the medium may be used for cryopreservation of the same cells the medium is intended for use in expanding cells, such as a cryopreservation medium composition comprising 50-90% medium and the cryoprotectant DMSO or glycerol ([0111]; [0154]). By incorporating the reference Zhao et al. 1994, Fong teaches the modified IL-2 (IL-2-IL-6) has similar biological activity as a naturally occurring IL-2 having at least 90% sequence homology ([0322]; [0014]). Zhao teaches IL-2-IL-6 (CH925)) comprises an identical sequence to a human IL-2 and has similar activity (Fig. 1, 7-8 and ; pg. 340, left col., 3rd para.).
Fong does not teach the or wherein the dose of IL-2-IL-6 in the medium is specifically within 0.1 to 1 mg per 100 mL (1-10 µg/mL).
However Zhao teaches using human IL-2 at 500 IU/mL (U/ml) in media for expanding cells in culture (pg. 341, right col., 4th para.; Fig. 7), which is equivalent to 0.1 µg/mL given the specific activity was 5 x 106 U/mg (pg. 344, left col., 2nd para.).
It would have been prima facia obvious to one of ordinary skill in the art at the effective time of filing to make the medium taught by Fong comprising a cryoprotectant and the modified IL-2-IL-6 wherein the concentration of IL-2-IL-6 is 0.9 µg/mL from using 90% of a medium comprising 0.1 µg/mL cytokine as taught by Fong for using IL-2. Furthermore with the motivation to achieve cryopreservation, it is within the skills of one of ordinary skill in the art to use routine optimization to adjust the cytokine concentration higher to 1 µg/mL working from a 0.9 µg/mL starting point as a results effective variable, especially in light of Fong teaching variability in cryopreservation components and their quantities were already established in the art ([0111]).
Regarding claim 3, as noted above Fong teaches the medium comprising the modified IL-2 fusokine (IL-2-IL-6), meaning the medium inherently comprises the cytokine IL-6.
Regarding claim 10, as noted above it would have been prima facia obvious to one of ordinary skill in the art at the effective time of filing to select the modified IL-2 concentration to be 500 IU/mL prior to 50-90% dilution, and thus Fong in view of Zhao teaches wherein the medium comprises 250-450 IU/mL IL-2, which is within 100 to 1 x109 International Units/mL. Note, a prima facie case of obviousness exists when the claimed range overlaps a value disclosed in the prior art. MPEP 2144.05. Thus, the claimed invention as a whole is prime facie obvious in the absence of evidence to the contrary.
Claims 21 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Fong (US 2013/0004648A1; IDS ref.) as evidenced by Wognum (Wognum, Mini-review Erythropoietin, STEMCELL Technologies (2015)) and Oster (Oster et al., Cancer 67(10 Suppl.): 2712-7 (1991)).
The claims are interpreted as set forth in a previous section.
Regarding claim 21, Fong teaches a cryopreservation medium comprising 50-90% of an expansion medium comprising the modified type 1 cytokine erythropoietin (Epo-IL-3) ([0018]; [0113]-[0115]; [0021]; [0068]) and 5-10% of the cryoprotectant DMSO ([0111]; [0154]). By incorporating the reference Lu et al. 1995, Fong discloses the modified EPO has similar biological activity as a naturally occurring human EPO having at least 90% sequence homology ([0322]; [0114]). As evidenced by Lu, Epo-IL-3 comprises an EPO component having 100% sequence identity to human EPO and a similar biological activity to human EPO which is maintained after fusion (Abstract).
Fong does not expressly teach wherein the concentration of modified EPO is 0.1 to 10 mg per 100 mL, i.e., 1-100 µg/mL. Instead, Fong teaches using a concentration of EPO in the expansion medium of about 1-30 IU/mL ([0133]), which for 30 IU/mL is equivalent to about 0.4 µg/mL as evidenced by Wognum teaching the specific activity of EPO being about 70,000 IU/mg (pg. 4, right col., 1st para.).
It would have been prima facia obvious to one of ordinary skill in the art at the effective time of filing to modify the medium taught by Fong comprising the cryoprotectant DMSO and the modified EPO (Epo-IL-3) to wherein the concentration of the Epo-IL-3 is 1 µg/mL or higher using routine experimentation. With the goal of cryopreservation, it is within the skills of one of ordinary skill in the art using routine experimentation to optimize the cytokine concentration higher from a starting concentration of Epo-IL-3 at 0.36 µg/mL from using 90% of a medium comprising 0.4 µg/mL cytokine as taught by Fong for using EPO and in light of Fong teaching variability in cryopreservation components and their quantities were already established in the art ([0111]).
Regarding claim 24, Fong does not expressly teach wherein the concentration of Epo-IL-3 in the medium is specifically within about 1x102 to 1x109 International Units/mL
However Fong teaches using IL-3 in the culture medium at a concentration of about 1-100 ng/mL, which with a specific activity of about 2 x 107 IU/mg (Oster at abstract), is equivalent to about 2 x 102 to 2 x 104 IU/mL.
It would have been prima facia obvious to one of ordinary skill in the art at the effective time of filing to make the medium taught by Fong comprising a cryoprotectant and the modified EPO (Epo-IL-3) wherein the concentration of Epo-IL-3 is 1.8 x 102 to 1.8 x 104 IU/mL from using 90% of a medium comprising 1-100 ng/mL cytokine as taught by Fong for using IL-3. Note, a prima facie case of obviousness exists when the claimed range overlaps a value disclosed in the prior art. MPEP 2144.05. Thus, the claimed invention as a whole is prime facie obvious in the absence of evidence to the contrary.
Response to arguments
Applicant traversed the previous anticipation rejection by arguing the claimed cryopreservation medium functions by reducing the injury of cells and tissues during freezing and thawing and protecting from damages associated with storage at sub-zero temperatures and/or freezing while Fong is silent to any cryopreservation medium. As noted above, Fong clearly discloses cryopreservation media comprising the cytokine(s) and notes cell cryopreservation media are known in the art for storing cells at less than 0, -70, -80, or -135 °C and that such media can be made by mixing the cell culture medium for multipotent immune progenitor cells with a known composition or cryoprotectant, such as a disaccharide, DMSO, serum albumin, and/or hetastarch ([0111]; [0154]).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638