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 .
The preliminary amendment filed 12/16/25 is acknowledged. Claims 1-24 have been canceled. Claims 25-39 have been added. Claims pending and under examination.
Claim Rejections - 35 USC § 112
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 33-39 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.
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.
Claim 33 is drawn to a composition comprising a gold nanoparticle, wherein the gold nanoparticle is bound to interleukin-2 (IL-2) and a cytokine configured to disrupt tumor vasculature.
The specification teaches that the term "cytokine" as used herein refers to a broad class of small proteins such as interferon, interleukin, and growth factors, which are secreted by certain cells of the immune system and have an effect on other cells. The specification teaches TNFα has been found to destroy the tumor vasculature. The specification discloses the manufacture of gold nanoparticles bound with TNFα, IFNγ, and PEG-thiol (CYT-TNFα-IFNγ).
The specification teaches the manufacture of gold nanoparticles bound by IL-2 (CYT-IL-2). The specification teaches that IL-2, TNF, and PEG-Thiol were introduced to a single solution of gold nanoparticles, thereby generating an IL-2-TNF dual agent gold nanoparticle.
Although the claims are inclusive of the gold nanoparticles comprising IL-2 and TNFα, the claims also broadly encompass gold nanoparticles comprising IL-2 and a cytokine that has the function of disrupting tumor vasculature. These nanoparticles have no correlation between their structure and function. The claims require that the cytokine that disrupt tumor vascular selectively induce permeability of tumor neovasculature. Further, the composition comprising the gold nanoparticle has the additional required functions of inducing clustering of receptors for IL-2 and receptors for the cytokine configured to disrupt tumor vasculature, on a cell surface. The specification defines the term cytokine to refer to the broad class of small proteins such as interferon, interleukin, and growth factors, which are secreted by certain cells of the immune system and have an effect on other cells. Given that the broad definition of the term “cytokine”, there are millions of possible compositions comprising the encompassed gold nanoparticles and “cytokine” that disrupts the tumor vasculature. However, the specification does not provide adequate guidance regarding specific cytokines that have the function of disrupting the tumor vasculature and can be bound to the gold nanoparticle to produce the required functions, and therefore, the specification provides insufficient written description to support the genus encompassed by the claims.
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the gold nanoparticles comprising IL-2 and TNFα, and the claimed functions, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed gold nanoparticle comprising IL-2 and TNFα, and encompass gold nanoparticles comprising IL-2 and any cytokine that disrupts the tumor vasculature. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a few species have been described and this is not considered to be representative of the breadth of the genus. Therefore, given the lack of structure function correlation and the lack of a representative number of species, the specification provides insufficient written description to support the genus encompassed by the claim.
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.)
With the exception of the gold nanoparticles comprising IL-2 and TNFα, the skilled artisan cannot envision the detailed chemical structure of the encompassed nanoparticles, regardless of the complexity or simplicity of the method of isolation. 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. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565,1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a given SEQ ID NO. will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the cytokine per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Applicant is reminded that generally, 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 (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 30-31 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 term “about” in claims 30-31 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Clarification and/or correction is required.
Claim Rejections - 35 USC § 102
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.
Claim(s) 25-28, 31, 33, and 34-38 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated Paciotti et al. (WO 2009/062151 A1, published May 14, 2009; herein referred to as Paciotti 2009) as evidenced by Paciotti et al. ((2004) Colloidal Gold: A Novel Nanoparticle Vector for Tumor Directed Drug Delivery, Drug Delivery, 11:3, 169-183; herein referred to as Paciotti 2004).
The instant claims are drawn to a composition comprising a gold nanoparticle, wherein the gold nanoparticle is covalently bound to a first cytokine and a second cytokine, the first cytokine comprises Tumor Necrosis Factor alpha (TNFa), and the second cytokine comprises Interleukin-2 (IL-2).
Paciotti 2009 teach a composition comprising a gold nanoparticle (cAu) comprising IL-2 and TNF (See pages 28-29 and figure 4b). Paciotti et al. teach that IL-2 contains multiple sulfhydryl and disulfide groups that form dative covalent bonds with the atoms of gold on the surface of gold nanoparticles (See page 20). As evidenced by Paciotti 2004, the sulhydryl groups present on the cysteine residues in TNF form a dative covalent bond with gold nanoparticles (See page 181). It should be noted that another name for thiol is a sulhydryl group (See Poole. Free Radic Biol Med. 2015 March; 0: 148–157). Paciotti 2009 teach that the composition comprises a heterofunctional PEG comprising a fluorescent detection molecule (See page 24). Paciotti 2009 teach that the gold nanoparticle comprises PEG-THIOL (See page 18). Paciotti 2009 teach that the size of the gold nanoparticle is 30-40 nm (See page 21). Paciotti 2009 teach that the molecular weight of the thiol-PEG has a PEG molecular weight of 5,000 to 30,000 daltons (See pages 23-24). Paciotti 2009 teach that the biologically active agents are bound to the gold nanoparticle via ionic bonds (See page 20).
Regarding the limitations “a cytokine configured to disrupt tumor vasculature” and “wherein the cytokine configured to disrupt tumor vasculature selectively induces permeability of tumor vasculature”, the instant specification teaches that TNF is a cytokines that disrupts tumor vasculature. Given that the prior art teaches the TNF cytokine, the property of disrupting tumor vasculature is necessarily present in the prior art. Regarding the limitations “wherein the composition is capable of clustering of receptors for IL-2 and receptors for the cytokine to disrupt tumor vasculature, on a cell surface”, the prior art composition comprises the components required by the instant claims, and therefore, the property of clustering receptors for IL-2 and receptors for the cytokine that disrupts the tumor vasculature would necessarily be present in the prior art. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. Thus, Paciotti 2009 anticipate the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 25-28, and 30-38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Paciotti et al. (WO 2009/062151 A1, published May 14, 2009, herein referred to as Paciotti 2009) as evidenced by Paciotti et al. ((2004) Colloidal Gold: A Novel Nanoparticle Vector for Tumor Directed Drug Delivery, Drug Delivery, 11:3, 169-183; herein referred to as Paciotti 2004).
The instant claims are drawn to a composition comprising a gold nanoparticle, wherein the gold nanoparticle is covalently bound to a first cytokine and a second cytokine, the first cytokine comprises Tumor Necrosis Factor alpha (TNFa), and the second cytokine comprises Interleukin-2 (IL-2).
Paciotti 2009 teach a composition comprising a gold nanoparticle (cAu) comprising IL-2 and TNF (See pages 28-29 and figure 4b). Paciotti 2009 teach that IL-2 contains multiple sulfhydryl and disulfide groups that form dative covalent bonds with the atoms of gold on the surface of gold nanoparticles (See page 20). As evidenced by Paciotti 2004, the sulhydryl groups present on the cysteine residues in TNF form a dative covalent bond with gold nanoparticles (See page 181). It should be noted that another name for thiol is a sulhydryl group (See Poole. Free Radic Biol Med. 2015 March; 0: 148–157). Paciotti 2009 teach that the composition comprises a heterofunctional PEG comprising a fluorescent detection molecule (See page 24). Paciotti 2009 teach that the gold nanoparticle comprises PEG-THIOL (See page 18). Paciotti 2009 teach that the size of the gold nanoparticle is 30-40 nm (See page 21). Paciotti 2009 teach that the molecular weight of the thiol-PEG has a PEG molecular weight of 5,000 to 30,000 daltons (See pages 23-24). Paciotti 2009 teach that the biologically active agents are bound to the gold nanoparticle via ionic bonds (See page 20).
Regarding the limitations “a cytokine configured to disrupt tumor vasculature” and “wherein the cytokine configured to disrupt tumor vasculature selectively induces permeability of tumor vasculature”, the instant specification teaches that TNF is a cytokines that disrupts tumor vasculature. Given that the prior art teaches the TNF cytokine, the property of disrupting tumor vasculature is necessarily present in the prior art. Regarding the limitations “wherein the composition is capable of clustering of receptors for IL-2 and receptors for the cytokine to disrupt tumor vasculature, on a cell surface”, the prior art composition comprises the components required by the instant claims, and therefore, the property of clustering receptors for IL-2 and receptors for the cytokine that disrupts the tumor vasculature would necessarily be present in the prior art. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.
Paciotti 2009 do not teach wherein a ratio of TNFα to IL-2, by weight is about 18:1 to about 22:1; and further comprising a polyethylene glycol-thiol, wherein a size of the polyethylene glycol-thiol is 2kDa to 20 kDa.
It would have been prima facie obvious before the effective filing date of the claimed invention to determine the ratio of TNFα to IL-2 on the gold nanoparticle since "it is the normal desire of scientists or artisans to improve upon what is already generally known". Paciotti 2009 teach a gold nanoparticle comprising both 1.5 µg/ml IL-2 and 100 ng/ml TNFα. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Regarding the size of the polyethylene glycol, Paciotti 2009 teach a range that encompasses the range recited in the instant claims. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Although Kakkar et al. teach a dose range that does not overlap, but is close, with the claimed dose range, Applicant has not demonstrated criticality of the claimed dose, and determining the optimal concentration COR-001 would be well within the knowledge of the skilled artisan.
Claim(s) 25, 27-31, 33, and 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Paciotti et al. (Cancer Res (2005) 65 (9_Supplement): 337–338; herein referred to as Paciotti 2005) in view of Tamarkin et al. (WO/9924077 A2, published May 20, 1999) and Pretto et al. (Cancer Immunol Immunother (2014) 63:901–910).
The instant claims are drawn to a composition comprising a gold nanoparticle, wherein the gold nanoparticle is covalently bound to a first cytokine and a second cytokine, the first cytokine comprises Tumor Necrosis Factor alpha (TNFa), and the second cytokine comprises Interleukin-2 (IL-2).
Paciotti 2005 teach AuriTax, a multivalent drug, assembled on 25 nm colloidal gold (cAu) particles and designed to deliver TNF and paclitaxel to solid tumors (See page 1). Paciotti 2005 teach that the drug is manufactured by covalently binding TNF, a thio-pyridyl derivative of paclitaxel, and thiolated polyethylene glycol (PEG-THIOL) onto the surface of cAu particles (See page 1). Paciotti 2005 teach that each component of the drug serves a specific function to achieve tumor targeted drug delivery. Paciotti 2005 teach the cAu particles limit the biodistribution of the drug by preferential extravasation of the leaky tumor neovasculature (See page 1). Paciotti 2005 teach the PEG-THIOL moiety hydrates the cAu particles and shields them from detection and clearance by the RES (See page 1). Paciotti 2005 teach TNF not only acts as one of the anti-tumor therapeutics delivered by AuriTax, but also as a targeting ligand, that binds to cell-surface receptors in and around the solid tumor (See page 1). Paciotti 2005 teach the paclitaxel derivative acts as a second therapeutic (See page 1). Paciotti 2005 teach that the gold nanoparticle comprising TNF and paclitaxel localized within solid tumors and sequences ten times the amount of TNF and paclitaxel compared to native drug treatment in the B16F10 melanoma mouse model (See page 2). Paciotti 2005 teach that the formulation also improved anti-tumor efficacy in vivo since it prevented the progression of B16F10 tumors in vivo, compared to animals receiving the native treatment, in which tumors continued to grow (See page 2).
Paciotti 2005 does not teach wherein the gold nanoparticle comprises IL-2 and wherein the ration of TNFα to IL-2, by weight, is about 18:1 to about 22:1.
Tamarkin et al. teach a gold nanoparticle comprising IL-2 for targeted delivery of biologically-active factors (See abstract and page 15-16). As evidenced by Paciotti 2009 (WO 2009/062151 A1, published May 14, 2009), IL-2 contains multiple sulfhydryl and disulfide groups that form dative covalent bonds with the atoms of gold on the surface of gold nanoparticles (See page 20). Tamarkin et al. teach that IL-2 is a specific stimulator of T cells (See page 25). Tamarkin et al. teach that the nanoparticle can be used to treat diseases, such as cancer, in which an immune response occurs, by stimulating or suppressing components that are part of the immune response (See page 28). Tamarkin et al. teach that IL-2 mixed with colloidal gold has little to no toxicity and induces a strong immune response (See page 31-32). Tamarkin et al. teach that the amount of biologically active factor released from the colloidal metal: biologically active factor complex is dependent upon the amount of biologically active factor initially bound to the colloidal metal (See page 32). Tamarkin et al. teach that more biologically-active factor is released in vivo from complex having a greater amount of biologically-active factor initially bound (See page 32). Tamarkin et al. teach the skilled artisan is able to control the amount of biologically-active factor delivered by varying the amount of biologically- active factor initially bound to the colloidal metal (See page 32).
Pretto et al. teach that IL-2 based immunocytokines can be combined with paclitaxel and TNF based immunotherapy for the treatment of melanoma (See page 901). Pretto et al. teach that the IL-2 immunocytokine localized to the tumor site to mediate tumor growth retardation, which was potentiated by the combination with paclitaxel (See page 901). Pretto et al. teach that IL-2 immunocytokine was also studied in combination with TNF-based immunocytokines, and the combination treatment was superior to the action of individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection (See page 901).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the gold nanoparticle of Paciotti 2005 by covalently adhering IL-2 to the gold nanoparticle to have prepared a gold nanoparticle functionalized with TNFα, IL-2, PEG-THIOL, and paclitaxel for targeted delivery of the agents to tumors for treating cancer. Paciotti 2005 has established that gold nanoparticle functionalized with TNFα, PEG-THIOL, and paclitaxel enhance the anti-tumor response in melanoma. Similarly, Pretto et al. teach that gold nanoparticles can be functionalized with IL-2 for targeted delivery of IL-2 and enhancing the immune response to tumors. One of ordinary skill in the art would be motivated to prepare a gold nanoparticle comprising TNFα, IL-2, PEG-THIOL, and paclitaxel for the benefit of improving the delivery of the agents to tumor and improving the anti-tumor response of each of the agents. One of ordinary skill in the art would have a reasonable expectation of success because both Paciotti 2005 and Tamarkin et al. teach that gold nanoparticles can be functionalized with multiple agents, and Pretto teach that IL-2 can be combined with paclitaxel and TNF based therapeutics to enhance the anti-tumor response in melanoma.
Regarding the ratio of TNFα to IL-2, Tamarkin et al. teach the skilled artisan is able to control the amount of biologically-active factor delivered by varying the amount of biologically- active factor initially bound to the colloidal metal. Thus, the art recognizes that the amount of TNFα and IL-2 bound to the gold nanoparticle is a result effective variable that can be optimized by one of ordinary skill in the art. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Although Kakkar et al. teach a dose range that does not overlap, but is close, with the claimed dose range, Applicant has not demonstrated criticality of the claimed dose, and determining the optimal concentration COR-001 would be well within the knowledge of the skilled artisan.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". The combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674