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 .
Claim Status
The amendments and arguments filed 11/7/25 are acknowledged. Claims 2, 4-6, 8, 15-17, 19-24, 26-28, 30-41, 43, 45, 49-51 are cancelled. Claims 1, 3, 7, 9-14, 18, 25, 29, 42, 44, and 46-48 are pending. Claims 44 and 46-48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/17/25.
Claims 1, 3, 7, 9-14, 18, 25, 29, and 42 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 11/7/25 have been considered. A signed copy is enclosed.
Declaration Under 37 CFR 1.130
The Declaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25 has been considered. The substance of the Declaration is addressed below.
Claim Rejections Withdrawn
The rejection of claim(s) 1, 3, 7, 9-11, 14, 29, and 42 under 35 U.S.C. 103 as being unpatentable over Callmann et al (Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17543-17550. doi: 10.1073/pnas.2005794117. Epub 2020 Jul 15) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144), as evidenced by Jordan (Cancer Letters 373 (2016) 88–96) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The rejection of claim(s) 1, 3, 7, 9-10, 12-14, 28, 29, and 42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al (Front Immunol. 2020 Jul 8:11:1333. doi: 10.3389/fimmu.2020.01333. eCollection 2020) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The provisional rejection of claims 1, 3, 7, 9-11, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 13, 15, 17-19, 24, 27, 30, 33, 41-45, 47-48 of copending Application No. 17/084,460 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Callmann et al (Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17543-17550. doi: 10.1073/pnas.2005794117. Epub 2020 Jul 15), as evidenced by Jordan (Cancer Letters 373 (2016) 88–96) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The provisional rejection of claims 1, 3, 7, 9-10, 12-14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8, 13, 15, 17-19, 24, 27, 30, 33, 41-45, 47-48 of copending Application No. 17/084,460 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Qin et al (Front Immunol. 2020 Jul 8:11:1333. doi: 10.3389/fimmu.2020.01333. eCollection 2020) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The provisional rejection of claims 1, 3, 7, 9-11, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-61 of copending Application No. 17/743,422 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Callmann et al (Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17543-17550. doi: 10.1073/pnas.2005794117. Epub 2020 Jul 15), as evidenced by Jordan (Cancer Letters 373 (2016) 88–96) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The provisional rejection of claims 1, 3, 7, 9-10, 12-14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-61 of copending Application No. 17/743,422 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Qin et al (Front Immunol. 2020 Jul 8:11:1333. doi: 10.3389/fimmu.2020.01333. eCollection 2020) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The provisional rejection of claims 1, 3, 7, 9-11, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-49 and 82-118 of copending Application No. 18/862,866 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Callmann et al (Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17543-17550. doi: 10.1073/pnas.2005794117. Epub 2020 Jul 15), as evidenced by Jordan (Cancer Letters 373 (2016) 88–96) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The provisional rejection of claims 1, 3, 7, 9-10, 12-14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-49 and 82-118 of copending Application No. 18/862,866 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Qin et al (Front Immunol. 2020 Jul 8:11:1333. doi: 10.3389/fimmu.2020.01333. eCollection 2020) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The provisional rejection of claims 1, 3, 7, 9-11, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 3-8, 13, 15, 17-19, 24, 27, 30, 33, 36, 41-46 of copending Application No. 18/949,786 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Callmann et al (Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17543-17550. doi: 10.1073/pnas.2005794117. Epub 2020 Jul 15), as evidenced by Jordan (Cancer Letters 373 (2016) 88–96) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
The provisional rejection of claims 1, 3, 7, 9-10, 12-14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 3-8, 13, 15, 17-19, 24, 27, 30, 33, 36, 41-46 of copending Application No. 18/949,786 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Qin et al (Front Immunol. 2020 Jul 8:11:1333. doi: 10.3389/fimmu.2020.01333. eCollection 2020) is withdrawn in light of the Delcaration of Chad A. Mirkin under 37 CFR 1.130 filed 11/7/25. The rejection of claim 28 is rendered moot by cancellation of the claim.
Claim Rejections Maintained
Claim Rejections - 35 USC § 112(a)
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.
The rejection of claims 1, 3, 7, 9-14, 18, 25, 29, and 42 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 are maintained. The rejection of claim 28 is rendered moot by cancellation of the claim. 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.
The instant claims are directed to spherical nucleic acids comprising a nanoparticle core, a TLR3 agonist encapsulated in the nanoparticle core, and a shell of oligonucleotides attached to the external surface of the nanoparticle core, wherein the shell comprises one or more TLR9 agonist oligonucleotides. The claims also recite an antigen that is bound to the nanoparticle core, which can be cancer related or a viral antigen. The claims also provide for one or more additional oligonucleotides encapsulated in the nanoparticle core that can have a function such as “therapeutic oligonucleotide” or “detection oligonucleotide”. The claims are also directed to an antigenic composition comprising the spherical nucleic acids in a composition that can generate an immune response including antibody generation or a protective immune response in a mammalian subject.
There are several issues with Written Description for the elected invention. First, the TLR3 agonists are not adequately described. The specification states that “Types of TLR3 agonists include, without limitation, polyinosinic:polycytidylic acid (poly(I:C)), polyadenylic:polyuridylic acid (poly(A:U)), double-stranded RNA, viral double stranded RNA, or a combination thereof” (see e.g. page 25 of the instant specification). However, the claims are not limited to these examples, and the specification does not limit the types of molecules that are encompassed by the claimed genus of agonists. Therefore, when given the broadest reasonable interpretation, the claims encompass all types of molecules including peptides, proteins, antibodies, small molecules, nucleic acids, and any other type of molecule. These molecules are described solely by their function of agonizing TLR3, and the specification does not provide a corresponding structure. Further, the specification does not provide a representative number of species for the breadth of the claimed genus.
Second, the TLR9 agonist oligonucleotides are not adequately described. According to the instant specification, the TLR9 agonist oligonucleotides can comprise “single-stranded DNA, double-stranded DNA, single-stranded RNA, double-stranded RNA, or a combination thereof.” While the term is generally regarded in the art to refer to short single strands of DNA or RNA molecule (see e.g. Thermo Fisher Scientific “What is an Oligo” downloaded from https://www.thermofisher.com/blog/behindthebench/what-is-an-oligo/ on 5/1/25), the instant specification defines “oligonucleotide” as being interchangeable with “polynucleotide”, which has a broader meaning than for the art recognized definition of an oligonucleotide. “Polynucleotides” include any chain of nucleotide monomers bound through covalent bonds. Therefore, the term “oligonucleotide” is interpreted to read on any type of polynucleotide. These molecules are described solely by their function of agonizing TLR9, and the specification does not provide a corresponding structure. Further, the specification does not provide a representative number of species for the breadth of the claimed genus.
Third, the additional elements of cancer related antigens and therapeutic oligonucleotides are not adequately described. These elements are only described according to their functions. It is noted that the specification does not name specific antigens for any type of cancer, or describe any oligonucleotide that is useful as a “therapeutic” for any specific disease or disorder.
The TLR3 agonists, TLR9 agonists, cancer related antigens, and therapeutic oligonucleotides have no correlation between their structure and function. The specification provides no guidance regarding which molecules are capable of the required function. Further, the specification does not provide a representative number of species for any of these genera. Therefore, 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 SNAs used in Example 1 that incorporate a specific TLR3 agonist (polyinosinic:polycytidylic acid, poly(I:C)) and a specific TLR9 agonist (CpG oligonucleotide) on a liposomal scaffold, the skilled artisan cannot envision the detailed chemical structure of the encompassed TLR3 agonists, TLR9 agonists, cancer related antigens, and therapeutic oligonucleotides, 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 USPQ2datl966.
Regarding the encompassed proteins and peptides, protein chemistry is one of the most unpredictable areas of biotechnology. This unpredictability prevents prediction of the effects that a given number or location of mutation will have on a protein (such as TNF or a cytokine) As taught by Skolnick et al (Trends Biotechnol. 2000 Jan;18(1):34-9), sequence based methods for predicting protein function are inadequate because of the multifunctional nature of proteins (see e.g. abstract). Further, just knowing the structure of the protein is also insufficient for prediction of functional sites (see e.g. abstract). Sequence to function methods cannot specifically identify complexities for proteins, such as gain and loss of function during evolution, or multiple functions possible within a cells (see e.g. page 34, right column). Skolnick advocates determining the structure of the protein, then identifying the functionally important residues since using the chemical structure to identify functional sites is more in line with how a protein actually works (see e.g. page 34, right column).
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 Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Further, Miosge (Proc Natl Acad Sci U S A. 2015 Sep 15;112(37):E5189-98) teach that Short of mutational studies of all possible amino acid substitutions for a protein, coupled with comprehensive
functional assays, the sheer number and diversity of missense mutations that are possible for proteins means that their functional importance must presently be addressed primarily by computational inference (see e.g. page E5189, left column). However, in a study examining some of these methods, Miosge shows that there is potential for incorrect calling of mutations (see e.g. page E5196, left column, top paragraph). The authors conclude that the discordance between predicted and actual effect of missense mutations creates the potential for many false conclusions in clinical settings where sequencing is performed to detect disease-causing mutations (see e.g. page E5195, right column, last paragraph). The findings in their study show underscore the importance of interpreting variation by direct experimental measurement of the consequences of a candidate mutation, using as sensitive and specific an assay as possible (see e.g. page E5197, left column, top paragraph). 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).
One key issue is the prediction of protein function based on sequence similarity, which could be one way to identify the proteins and peptides that are useful in the instant claims. Kulmanov et al (Bioinformatics, 34(4), 2018, 660–668), teach that there are key challenges for protein function prediction methods (see e.g. page 661, left column). These challenges arise from the difficulty identifying and accounting for the complex relationship between protein sequence structure and function (see e.g. page 661, left column). Despite significant progress in the past years in protein structure prediction, it still requires large efforts to predict protein structure with sufficient quality to be useful in function prediction (see e.g. page 661, left column). Another challenge is that proteins do not function in isolation. In particular higher level physiological functions that go beyond simple molecular interactions will require other proteins and cannot usually be predicted by considering a single protein in isolation (see e.g. page 661, left column). Due to these challenges it is not obvious what kinds of features should be used to predict the functions of a protein and whether they can be generated efficiently for a large number of proteins, such as the vast genus of proteins and peptides encompassed by the instant claims (see e.g. page 661, left column).
Regarding the encompassed antibodies and antigen binding fragments thereof, the functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements. Therefore, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding small molecule inhibitors of a particular protein target, the prediction of binding to a target, much less the inhibitory activity, is highly unpredictable. According to Guido et al (Curr Med Chem. 2008;15(1):37-46), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may bind to a given target, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al (J. Med. Chem., 2014, 57 (12), pp 5023–5038), even when guided by structural data, developing selective structure-activity relationships has been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to inhibit a particular protein, especially a particular protein family member, or treat disease.
Regarding nucleic acid based therapeutics, the efficacy of any possible DNA or RNA based therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence the expression or function of any target. As taught by Aagaard et al (Advanced Drug Delivery Reviews 59 (2007) 75–86), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al (Leukemia and Lymphoma (1997) Vol. 24. pp. 267-281) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three dimensional RNA structures (see page 269), while DNA-targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. McKeague et al (J Nucleic Acids. 2012;2012:748913. Epub 2012 Oct 24) teach that aptamers have particular challenges because unlike antibodies or molecular imprinted polymers, their tertiary structure is highly dependent on solution conditions and they are easily degraded in blood. Further, they have less chemical diversity than other antagonist molecules (see page 2), and have issues associated with determining the Kd measurements for a given molecule (see page 13). Given the teachings of Aagaard et al, Warzocha et al, and McKeague et al, the claimed nucleic acid therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed nucleic acid based therapeutic, such as oligonucleotide aptamers, RNAi molecules and antisense oligonucleotides, would function to decrease expression or function of a target gene or protein, or treat disease.
The claims encompass DNA and RNA molecules, which would include antisense, miRNA, siRNA, shRNA, and other molecules, each of which have distinct chemical and physical properties. Additionally, each type of molecule would require a different sequence to perform the required function. The efficacy of any possible nucleic acid modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence on the expression or function of any target. For example, as taught by Takasaki (Methods Mol Biol. 2013;942:17-55), while siRNA has been widely used for studying gene function, these molecules can vary markedly in gene silencing efficacy (see abstract). Although many design rules and guidelines for effective siRNAs based on various criteria have been reported, the effectiveness of an siRNA molecule varies widely depending on the target sequence selected from the target gene (see page 18). Even using the consistencies among the reported selection rules may cause the generation of candidate target sequences that are effective in silencing the gene. These rules therefore cannot estimate the probability that a candidate siRNA will actually silence the target gene (see page 18). According to Martinez-Sanchez et al (Biology 2013, 2, 189-205), identifying miRNA targets is also highly unpredictable. This difficulty and the complexity of miRNA binding to targets has resulted in the generation of a wide variety of experimental approaches (see page 190). In fact, the exact mechanisms used by miRNAs to regulate gene expression remain unclear and have been controversial subject in recent years (see page 191).
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.
Applicant’s Arguments
Applicant argues:
1. Applicant asserts that the specification provides comprehensive written description support for the claimed subject matter through detailed structural descriptions, specific synthesis methods and extensive experimental validation. The TLR3 agonists include poly (I:C), poly (A:U) viral double stranded RNA or a combination thereof. The specification provides the structural characteristics of poly (I:C).
2. Applicant asserts that for TLR9 agonist oligonucleotides, the specification points to a “CpG-motif” as a cytosine-guanine dinucleotide sequence and identifies CpG-motif containing oligonucleotides as examples. Example 1 provides actual reduction to practice.
3. Applicant asserts that the specification provides comprehensive synthesis protocols, including detailed methods for preparing poly(I:C) liposomes.
4. Applicant asserts that for the antigen components recited in claims 7 and 9-13, the specification defines the antigens as a peptide, a protein or a combination thereof and specifies that the antigen is a cancer related antigen or viral antigen including tumor cell lysate and prostate cancer antigen.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. First, Applicant fails to recognize that the Examiner has indicated that the poly(I:C) from Example 1 of the instant specification is adequately described.
Second, Applicant is attempting to read limitations from the specification into the claims. As stated in MPEP 2145, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The specification states that “Types of TLR3 agonists include, without limitation, polyinosinic:polycytidylic acid (poly(I:C)), polyadenylic:polyuridylic acid (poly(A:U)), double-stranded RNA, viral double stranded RNA, or a combination thereof” (see e.g. page 25 of the instant specification). The key term in this sentence is “include”. This term is not limiting, and indicates that in fact, the genus encompasses a much broader range of species than those that are specifically named as examples. The claims are not limited to the examples in the specification, and the specification does not limit the types of molecules that are encompassed by the claimed genus of agonists. Therefore, when given the broadest reasonable interpretation, the claims encompass all types of molecules including peptides, proteins, antibodies, small molecules, nucleic acids, and any other type of molecule. These molecules are described solely by their function of agonizing TLR3, and the specification does not provide a corresponding structure. Further, the specification does not provide a representative number of species for the breadth of the claimed genus.
2. Similar to the arguments for the TLR3 agonists, Applicant fails to recognize that the Examiner has indicated that the specific TLR9 agonist (CpG oligonucleotide) from Example 1 is described.
Further, Applicant is attempting to read limitations from the specification into the claims. As stated in MPEP 2145, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The specification states that “in some embodiments, each of the one or more TLR9 agonist oligonucleotides is a CpG-motif containing oligonucleotide.” The key term phrase here is “in some embodiments” indicating mere examples that, while encompassed by the instant claims, do not limit the instant claim scope.
Instead, the TLR9 agonist encompasses an enormous genus of possible oligonucleotides. TLR9 agonist oligonucleotides can comprise “single-stranded DNA, double-stranded DNA, single-stranded RNA, double-stranded RNA, or a combination thereof.” While the term is generally regarded in the art to refer to short single strands of DNA or RNA molecule (see e.g. Thermo Fisher Scientific “What is an Oligo” downloaded from https://www.thermofisher.com/blog/behindthebench/what-is-an-oligo/ on 5/1/25), the instant specification defines “oligonucleotide” as being interchangeable with “polynucleotide”, which has a broader meaning than for the art recognized definition of an oligonucleotide. “Polynucleotides” include any chain of nucleotide monomers bound through covalent bonds. Therefore, the term “oligonucleotide” is interpreted to read on any type of polynucleotide. These molecules are described solely by their function of agonizing TLR9, and the specification does not provide a corresponding structure. Further, the specification does not provide a representative number of species for the breadth of the claimed genus.
3. The Examiner agrees that assays exist to screen for agonist agents that perform specific functions. However, the skilled artisan cannot envision the detailed chemical structure of the encompassed agonist molecules, 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 description of the molecule 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. MPEP 2163 states that “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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. In the instant case, the functional characteristics are given without describing the correlation with a particular structure for the antibody. Binding of an antibody to the antigens described (MMP-7 and the zinc immunogen found in claims 11 and 27) are supported. It is the requirement for specific functions that are not present within the entire encompassed genus of antibodies that necessitates the rejection. In other words, not every molecule that binds or interacts with TLR3 or TLR9 will be an agonist that is capable of the required functions of the claims.
The arguments related to screening are more properly addressed to the enablement requirement under 35 USC 112(a). According to MPEP 2164.01, any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. Determining whether one of skill in the art could screen for appropriate agonists is a question of whether the skilled artisan could make and use the invention. The Examiner agrees that the invention is enabled, and as a result this issue has not been raised in a rejection.
Instead, the instant claims are rejected because the claims recite functional language without providing a corresponding required structure. A particular agent structure may be known to one of skill in the art, but Applicant is requiring the agents in the instant claims to have specific functional features that limit the embodiments to a sub-genus of agents having those functions, which are encompassed within the larger genus that have the required target molecule. One of skill in the art would not be able to “immediately envisage” the agonists within the claimed genus that have the required functional characteristics without extensive further experimentation. It is the recitation of functional language in the claims that necessitates the rejection.
While Applicant is entitled to use functional language in the description of claimed agents, according to MPEP 2163, an invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. This matches the facts here. The claims require specific functionality for the claimed agonists, but neither the instant disclosure, nor the art, provide description of the corresponding structure for that functionality or a representative number of species for the agents. Even when given possible species from which to select an appropriate agonist molecule, the question remains about which one(s) of the encompassed species would actually perform the claimed function. While one of skill in the art could likely screen for agonists having the required functions, the mere fact that experimentation is necessary to identify the members of the genus indicates that proper description has not been provided.
4. Even in the arguments, Applicant fails to point to evidence that suggests that the cancer or viral antigens are defined by anything more than their general structures as peptides or proteins. Even knowing that they can be peptides or proteins, Applicant has not provided any criteria for identifying whether an antigen is a “cancer-related antigen” or “viral antigen”. There is no means for identifying species with in the enormous genus of “protein or peptide” that have the specific functions of being “cancer related” or “viral” antigens. These elements are only described according to their functions. It is noted that the specification does not name specific antigens for any type of cancer, or describe any oligonucleotide that is useful as a “therapeutic” for any specific disease or disorder.
The TLR3 agonists, TLR9 agonists, cancer related antigens, and therapeutic oligonucleotides have no correlation between their structure and function. The specification provides no guidance regarding which molecules are capable of the required function. Further, the specification does not provide a representative number of species for any of these genera. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Claim Rejections - 35 USC § 112(b)
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.
The rejection of claims 9, 13, and 29 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 is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim. The rejection of claim 42 is withdrawn in light of Applicant’s arguments thereto.
The term “cancer-related” in claim 9 is a relative term which renders the claim indefinite. The term “cancer-related” 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. The specification does not present criteria to distinguish between “cancer-related” antigens and antigens that are not “cancer-related”. Many antigens are present on both cancerous and healthy cells. The disclosure does not identify which of these antigens might be “cancer-related”. Therefore the claim scope is indefinite.
The term “prostate cancer antigen” in claim 13 is a relative term which renders the claim indefinite. The term “prostate cancer antigen” 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. The specification does not present criteria to distinguish between “prostate cancer antigens” and antigens that are not “prostate cancer antigens”. Many antigens are present on both cancerous and healthy cells. The disclosure does not identify which of these antigens might be “prostate cancer antigens”. Therefore the claim scope is indefinite.
In claim 29, the phrases “therapeutic oligonucleotide” and “detection oligonucleotide” render the claim scope indefinite. These terms are not defined by the specification, and no criteria are set forth to identify any oligonucleotide as “therapeutic” or as “detectable”. It is further unclear whether mRNA and plasmid DNA molecules are encompassed by the terms “therapeutic oligonucleotide” and “detection oligonucleotide” or if these terms are limited to molecules that are not mRNA or plasmid DNA.
Applicant’s Arguments
Applicant argues:
1. Applicant argues that the term “cancer related antigen” is not indefinite and is established as antigens associated with or expressed by cancer cells. The specification lists specific cancer types which provides teachings specific enough for one of skill in the art to understand the antigens are those associated with enumerated cancer types.
2. Prostate cancer antigen is not indefinite, and would be understood as antigens associated with prostate cancer. Applicant points to paragraph [0079] which says that in some embodiments the antigen is attached to eh surface of the nanoparticle core, and also points out that prostate cancer is one of the cancer types that is specifically listed in the disclosure.
3. Regarding claim 29, the phrases “therapeutic oligonucleotide” and “detection oligonucleotide” are not indefinite. Applicant points to paragraph [0046] and [0054] of the instant specification.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. The term “cancer related antigens” is not definite. Even in the arguments, Applicant relies on vague terms such as “associated with”. The term “associated with” only requires some connection, without determining the type of connection required. Additionally, the term “cancer-related” is not defined by the specification. The term “related” could mean antigens specifically expressed by cancer, or it could mean antigens that are in some way connected with cancer. This raises a number of questions, such as, if a protein is expressed in the body without the cancer present, is the antigen still considered “cancer-related”? Furthermore, it is unclear how one of skill in the art would identify antigens that are specifically “cancer-related”. For example, cancers express many of the same proteins that are expressed on non-cancerous cells. There is no way to identify which of these expressed potential antigens would fall within the definition of “cancer-related” antigens.
2.As stated above, Applicant relies on vague terms such as “associated with”. The term “associated with” only requires some connection, without determining the type of connection required. Second, the specification does not present criteria to distinguish between “prostate cancer antigens” and antigens that are not “prostate cancer antigens”. Many antigens are present on both cancerous and healthy cells. The disclosure does not identify which of these antigens might be “prostate cancer antigens”. Therefore the claim scope is indefinite. Naming a specific type of cancer does not identify the antigens that are “associated with” that cancer. Furthermore, paragraph [0079], which Applicant points to for support, only offers “in some embodiments” language, which is merely exemplary and does not define the scope of the encompassed antigens. Further, there are no criteria set forth that would allow one of skill in the art to identify the encompassed prostate cancer antigens, or to distinguish the “cancer” antigens from the non-cancer antigens.
3. Applicant relies on sweeping language and exemplary language to identify a genus of molecules that are defined only by function, and for which even the function is not clearly described. There is no identification what type of disease or condition is being treated, or by what criteria “therapeutic” effect or “detection” function is measured. Any oligonucleotide could potentially be encompassed, or very few could be encompassed, depending on how the terms “therapeutic” or “detection” are defined. In other words, the terms are relative terms. Without having a clear scope defined by criteria for identifying the encompassed agents, the terms are indefinite.
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.
1. The rejection of claim(s) 1, 3, 7, 9, 14, 18, 25, 29, and 42 under 35 U.S.C. 103 as being unpatentable over Nallagatla et al (WO 2017/193084 A1; filed 5/5/17; published 11/9/17) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claims.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
Nallagatla teaches immunostimulatory spherical nucleic acids (IS-SNA) for the treatment of cancer (see e.g. abstract, claim 35 and 55). The immunostimulatory oligonucleotide in the IS-SNA can increase the ratio of T-effector cells to T-regulatory cells relative to a linear immunostimulatory oligonucleotide not bound to an IS-SNA (see e.g. claim 50). The IS-SNA can target a TLR9 receptor in a cell (see e.g. claim 52). The IS-SNA can comprise an oligonucleotide shell comprised of immunostimulatory oligonucleotides positioned on the exterior of the core in an amount effective to treat cancer (see e.g. claim 55). The immunostimulatory oligonucleotides can be CpG oligonucleotides (see e.g. claim 63). According to the instant specification, CpG-motif oligonucleotides meet the limitations of the claims for a TLR9 agonist oligonucleotide (see e.g. instant specification page 3, line 1). According to Nallagatla, the shell can be comprised of combinations of different types of oligonucleotides, including a mixture of A-, B-, and C-class CpG oligonucleotides, which would meet the limitations for both the TLR9 agonist oligonucleotide, and the additional oligonucleotide in the nanoparticle shell as required by the instant claims (see e.g. claim 67, page 6, lines 15-25). The IS-SNA can comprise a liposomal core (see e.g. page 23, lines 20-34, claim 35, claim 59). The nanostructures of Nallagatla can be composed of nanoparticles having a core and a shell of oligonucleotides, which is formed by arranging CpG oligonucleotides such that they point radially outwards from the core (see e.g. page 22, lines 1-12). A hydrophobic (e.g. lipid) anchor group attached to either the 5' - or 3 '-end of the oligonucleotide, depending on whether the 5 oligonucleotides are arranged with the 5' - or 3 '-end facing outward from the core preferably is used to embed the oligonucleotides to a lipid based nanoparticle (see e.g. page 22, lines 1-12). The anchor acts to drive insertion into the lipid nanoparticle and to anchor the oligonucleotides to the lipids (see e.g. page 22, lines 1-12). The IS-SNA may be modified to include a cancer antigen (see e.g. page 26, lines 10-16). The IS-SNA can be designed to include peptides, proteins, or targeting antibodies along with the oligonucleotides on the nanoparticle, wherein the peptide or protein can be a cancer antigen (see e.g. page 26, lines 15-20; page 37, lines 1-10). The IS-SNA can be present in a pharmaceutical composition with a carrier and various excipients (see e.g. page 29, lines 14-30).
Nallagatla does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of Nallagatla to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of Nallagatla would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of Nallagatla, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of Nallagatla to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of Nallagatla is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt provides an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt and Nallagatla therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt into the liposome of Nallagatla, one would achieve an enhanced immunotherapeutic for treating cancer.
Applicant’s Arguments
Applicant argues:
1. Applicant argues that Nallagatla is silent regarding TLR3 agonists encapsulated within the nanoparticle core, and points to Nallagatla describing that the nanostructures are typically composed of nanoparticles having a core and a shell of oligonucleotides. These disclosures do not suggest encapsulating TLR3 agonists within the core structure, and Applicant asserts that there is no disclosure in Nallagatla suggesting encapsulation of any substance.
Further, Bayyurt requires that both TLR ligands are co-encapsulated within a liposome, which is fundamentally different from the claimed structure of the instant claims, where one or more TLR3 agonists are encapsulated in a nanoparticle core, while one or more TLR9 agonist oligonucleotides form the external shell. Bayyurts approach involves having both ligands co-encapsulated to achieve simultaneous delivery to innate immune cells. Such a combination would not suggest the SNA recited in the instant claims, because Nallagatla’s architecture is specifically designed for surface presentation of immunostimulatory oligonucleotides.
2. The nanoparticles of the instant claims target activation of different TLR pathways that are not disclosed or suggested by the combination of the cited documents.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. Applicant is attempting to argue the limitations of the references individually, without addressing the combined teachings. As stated in MPEP 2145, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Nallagatla specifically provides for the same type of structure as Bayyurt, including liposomes (see e.g. claim 5 of Nallagatla), and specifically describes encapsulating substances (see e.g. page 29, line 30). The instant specification identifies liposomes as an appropriate nanoparticle (for example, see e.g. instant specification paragraphs [0015]-[0016]). Bayyurt provides evidence of the specific type of compounds that should be combined in the core of the nanoparticle, which can also be a liposome, similar to Nallagatla, to achieve maximum therapeutic effect.
Applicant is reminded that the instant claims recite the transitional phrase “comprising” which is open-ended and allows for additional substances to be attached or encompassed by the claimed SNA. This term “comprising” specifically encompasses all types of additional substances in the SNA, including those not specifically claimed, and this includes the possibility that multiple substances could be present in the core. The claims further explicitly do not exclude any specific additional substances. The two-agent core of Bayyurt would therefore be encompassed by the instant claims. Furthermore, the existence of Bayyurt’s core does not require disruption of the structure of Nallagatla’s particles. Applicant has failed to acknowledged that both Nallagatla’s surface presentation architecture, AND Bayyurt’s core could be present as described. There is no limitation either in the instant claims or in Nallagatla that would exclude multiple molecules from being present in the particle core.
2. Applicant is arguing limitations that are not claimed. The instant claims do not recite a requirement to activate a specific pathway. According to MPEP 2145, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993)
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The rejection of claims 1, 3, 7, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent 12,378,560, previously copending Application No. 17/084,460 (reference application), in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) is maintained. The copending application has been patented, and therefore the rejection is no longer provisional. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The reference claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core, wherein the oligonucleotide shell comprises a mixture of Class A and Class B CpG Oligonucleotide (see e.g. claim 1 and 2). The SNA can further comprise an inhibitory oligonucleotide (see e.g. claim 10-11). The nanoparticle can be a liposome (see e.g. claim 12). The SNA can further comprise an additional agent such as a protein, peptide or small molecule (see e.g. claim 13). The reference claims further teach a method of treating a disorder with the SNA (see e.g. claim 20-23). The disorder can be cancer (see e.g. claim 23).
The reference patent does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the reference patent to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the reference patent would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the reference patent, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the reference patent to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the reference patent is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt provides an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt and the reference patent therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt into the liposome of the reference patent, one would achieve an enhanced immunotherapeutic for treating cancer.
The provisional rejection of claims 1, 3, 7, 9, 14, 18, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent 12,378,560, previously copending Application No. 17/084,460 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Nallagatla et al (WO 2017/193084 A1; filed 5/5/17; published 11/9/17) is maintained. The copending application has been patented, and therefore the rejection is no longer provisional. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The reference claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core, wherein the oligonucleotide shell comprises a mixture of Class A and Class B CpG Oligonucleotide (see e.g. claim 1 and 2). The SNA can further comprise an inhibitory oligonucleotide (see e.g. claim 10-11). The nanoparticle can be a liposome (see e.g. claim 12). The SNA can further comprise an additional agent such as a protein, peptide or small molecule (see e.g. claim 13). The reference claims further teach a method of treating a disorder with the SNA (see e.g. claim 20-23). The disorder can be cancer (see e.g. claim 23).
The reference patent does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
The reference patent and Bayyurt do not teach that the composition also includes a cancer antigen, or that the antigen is attached to the oligonucleotide in the shell through a lipid anchor.
Nallagatla teaches immunostimulatory spherical nucleic acids (IS-SNA) for the treatment of cancer (see e.g. abstract, claim 35 and 55). The immunostimulatory oligonucleotide in the IS-SNA can increase the ratio of T-effector cells to T-regulatory cells relative to a linear immunostimulatory oligonucleotide not bound to an IS-SNA (see e.g. claim 50). The IS-SNA can target a TLR9 receptor in a cell (see e.g. claim 52). The IS-SNA can comprise an oligonucleotide shell comprised of immunostimulatory oligonucleotides positioned on the exterior of the core in an amount effective to treat cancer (see e.g. claim 55). The immunostimulatory oligonucleotides can be CpG oligonucleotides (see e.g. claim 63). According to the instant specification, CpG-motif oligonucleotides meet the limitations of the claims for a TLR9 agonist oligonucleotide (see e.g. instant specification page 3, line 1). According to Nallagatla, the shell can be comprised of combinations of different types of oligonucleotides, including a mixture of A-, B-, and C-class CpG oligonucleotides, which would meet the limitations for both the TLR9 agonist oligonucleotide, and the additional oligonucleotide in the nanoparticle shell as required by the instant claims (see e.g. claim 67, page 6, lines 15-25). The IS-SNA can comprise a liposomal core (see e.g. page 23, lines 20-34, claim 35, claim 59). The nanostructures of Nallagatla can be composed of nanoparticles having a core and a shell of oligonucleotides, which is formed by arranging CpG oligonucleotides such that they point radially outwards from the core (see e.g. page 22, lines 1-12). A hydrophobic (e.g. lipid) anchor group attached to either the 5' - or 3 '-end of the oligonucleotide, depending on whether the 5 oligonucleotides are arranged with the 5' - or 3 '-end facing outward from the core preferably is used to embed the oligonucleotides to a lipid based nanoparticle (see e.g. page 22, lines 1-12). The anchor acts to drive insertion into the lipid nanoparticle and to anchor the oligonucleotides to the lipids (see e.g. page 22, lines 1-12). The IS-SNA may be modified to include a cancer antigen (see e.g. page 26, lines 10-16). The IS-SNA can be designed to include peptides, proteins, or targeting antibodies along with the oligonucleotides on the nanoparticle, wherein the peptide or protein can be a cancer antigen (see e.g. page 26, lines 15-20; page 37, lines 1-10). The IS-SNA can be present in a pharmaceutical composition with a carrier and various excipients (see e.g. page 29, lines 14-30).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the reference patent to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the reference patent would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the reference patent, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the reference patent to incorporate poly I:C and CpG ODN of Bayyurt and the lipid-anchored antigen of Nallagatla in the liposome because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the reference patent is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt and Nallagatla provide an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt, Nallagatla and the reference patent therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt and Nallagatla into the liposome of the reference patent, one would achieve an enhanced immunotherapeutic for treating cancer.
The provisional rejection of claims 1, 3, 7, 9-10, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 18, 21, 31-34, 41, 44-45, 49-50, 53, 57, 59, 61 and 68 of copending Application No. 17/684,269 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The copending claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core, wherein the oligonucleotide shell comprises a one or more immunostimulatory oligonucleotides (see e.g. claim 1). The shell can comprise a combination of DNA and RNA, indicating that more than one oligonucleotide can be present (see e.g. claim 18). The immunostimulatory oligonucleotide can be CpG-motif oligonucleotide (see e.g. claim 44). The SNA comprises a viral antigen encapsulated in the nanoparticle core (see e.g. claim 1). The copending claims further teach a method of treating a disorder with the SNA (see e.g. claim 57). The SNA can be present in an antigenic composition that comprises a carrier, diluent, etc. (see e.g. claim 50.
The copending application does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the copending application would generate liposomes that have greater immune stimulating capabilities to treat infection. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the copending application, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the copending application is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system. Bayyurt provides an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt and the copending application therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
The provisional rejection of claims 1, 3, 7, 9-10, 14, 18, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 18, 21, 31-34, 41, 44-45, 49-50, 53, 57, 59, 61 and 68 of copending Application No. 17/684,269 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Nallagatla et al (WO 2017/193084 A1; filed 5/5/17; published 11/9/17) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The copending claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core, wherein the oligonucleotide shell comprises a one or more immunostimulatory oligonucleotides (see e.g. claim 1). The shell can comprise a combination of DNA and RNA, indicating that more than one oligonucleotide can be present (see e.g. claim 18). The immunostimulatory oligonucleotide can be CpG-motif oligonucleotide (see e.g. claim 44). The SNA comprises a viral antigen encapsulated in the nanoparticle core (see e.g. claim 1). The copending claims further teach a method of treating a disorder with the SNA (see e.g. claim 57). The SNA can be present in an antigenic composition that comprises a carrier, diluent, etc. (see e.g. claim 50.
The copending application does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
The copending application and Bayyurt do not teach that the composition also includes a cancer antigen, or that the antigen is attached to the oligonucleotide in the shell through a lipid anchor.
Nallagatla teaches immunostimulatory spherical nucleic acids (IS-SNA) for the treatment of cancer (see e.g. abstract, claim 35 and 55). The immunostimulatory oligonucleotide in the IS-SNA can increase the ratio of T-effector cells to T-regulatory cells relative to a linear immunostimulatory oligonucleotide not bound to an IS-SNA (see e.g. claim 50). The IS-SNA can target a TLR9 receptor in a cell (see e.g. claim 52). The IS-SNA can comprise an oligonucleotide shell comprised of immunostimulatory oligonucleotides positioned on the exterior of the core in an amount effective to treat cancer (see e.g. claim 55). The immunostimulatory oligonucleotides can be CpG oligonucleotides (see e.g. claim 63). According to the instant specification, CpG-motif oligonucleotides meet the limitations of the claims for a TLR9 agonist oligonucleotide (see e.g. instant specification page 3, line 1). According to Nallagatla, the shell can be comprised of combinations of different types of oligonucleotides, including a mixture of A-, B-, and C-class CpG oligonucleotides, which would meet the limitations for both the TLR9 agonist oligonucleotide, and the additional oligonucleotide in the nanoparticle shell as required by the instant claims (see e.g. claim 67, page 6, lines 15-25). The IS-SNA can comprise a liposomal core (see e.g. page 23, lines 20-34, claim 35, claim 59). The nanostructures of Nallagatla can be composed of nanoparticles having a core and a shell of oligonucleotides, which is formed by arranging CpG oligonucleotides such that they point radially outwards from the core (see e.g. page 22, lines 1-12). A hydrophobic (e.g. lipid) anchor group attached to either the 5' - or 3 '-end of the oligonucleotide, depending on whether the 5 oligonucleotides are arranged with the 5' - or 3 '-end facing outward from the core preferably is used to embed the oligonucleotides to a lipid based nanoparticle (see e.g. page 22, lines 1-12). The anchor acts to drive insertion into the lipid nanoparticle and to anchor the oligonucleotides to the lipids (see e.g. page 22, lines 1-12). The IS-SNA may be modified to include a cancer antigen (see e.g. page 26, lines 10-16). The IS-SNA can be designed to include peptides, proteins, or targeting antibodies along with the oligonucleotides on the nanoparticle, wherein the peptide or protein can be a cancer antigen (see e.g. page 26, lines 15-20; page 37, lines 1-10). The IS-SNA can be present in a pharmaceutical composition with a carrier and various excipients (see e.g. page 29, lines 14-30).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the copending application would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the copending application, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt and the lipid-anchored antigen of Nallagatla in the liposome because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the copending application is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt and Nallagatla provide an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt, Nallagatla and the copending application therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt and Nallagatla into the liposome of the copending application, one would achieve an enhanced immunotherapeutic for treating cancer.
The provisional rejection of claims 1, 3, 7, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-68 of copending Application No. 17/743,422 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The copending claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core (see e.g. claim 1 and 2). The SNA comprises an antigen that can be encapsulated in the nanoparticle core or attached to one or more oligonucleotides in the shell through a linker or attached to the surface of the nanoparticle core through a linker (see e.g. claim 4). The oligonucleotide shell comprises immunostimulatory oligonucleotide such as a TLR9 agonist (see e.g. claim 7-11). The oligonucleotide can comprise a CpG nucleotide sequence (see e.g. claim 12). The nanoparticle can be a liposome (see e.g. claim 17-18). The shell of oligonucleotides can comprise DNA in combination with RNA, indicating that more than one oligonucleotide can be present in the shell (see e.g. claim 23-24). The SNA can comprise a tumor antigen (see e.g. claim 35). The SNA can be present in an antigenic composition in a carrier, diluent, etc. (see e.g. claim 41). The copending claims further teach a method of treating a disorder with the SNA (see e.g. claim 52). The disorder can be cancer (see e.g. claim 53), including prostate cancer (see e.g. claim 55).
The copending application does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the copending application would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the copending application, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the copending application is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt provides an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt and the copending application therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt into the liposome of the copending application, one would achieve an enhanced immunotherapeutic for treating cancer.
The provisional rejection of claims 1, 3, 7, 9, 14, 18, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-68 of copending Application No. 17/743,422 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Nallagatla et al (WO 2017/193084 A1; filed 5/5/17; published 11/9/17) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The copending claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core (see e.g. claim 1 and 2). The SNA comprises an antigen that can be encapsulated in the nanoparticle core or attached to one or more oligonucleotides in the shell through a linker or attached to the surface of the nanoparticle core through a linker (see e.g. claim 4). The oligonucleotide shell comprises immunostimulatory oligonucleotide such as a TLR9 agonist (see e.g. claim 7-11). The oligonucleotide can comprise a CpG nucleotide sequence (see e.g. claim 12). The nanoparticle can be a liposome (see e.g. claim 17-18). The shell of oligonucleotides can comprise DNA in combination with RNA, indicating that more than one oligonucleotide can be present in the shell (see e.g. claim 23-24). The SNA can comprise a tumor antigen (see e.g. claim 35). The SNA can be present in an antigenic composition in a carrier, diluent, etc. (see e.g. claim 41). The copending claims further teach a method of treating a disorder with the SNA (see e.g. claim 52). The disorder can be cancer (see e.g. claim 53), including prostate cancer (see e.g. claim 55).
The copending application does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
The copending application and Bayyurt do not teach that the composition also includes a cancer antigen, or that the antigen is attached to the oligonucleotide in the shell through a lipid anchor.
Nallagatla teaches immunostimulatory spherical nucleic acids (IS-SNA) for the treatment of cancer (see e.g. abstract, claim 35 and 55). The immunostimulatory oligonucleotide in the IS-SNA can increase the ratio of T-effector cells to T-regulatory cells relative to a linear immunostimulatory oligonucleotide not bound to an IS-SNA (see e.g. claim 50). The IS-SNA can target a TLR9 receptor in a cell (see e.g. claim 52). The IS-SNA can comprise an oligonucleotide shell comprised of immunostimulatory oligonucleotides positioned on the exterior of the core in an amount effective to treat cancer (see e.g. claim 55). The immunostimulatory oligonucleotides can be CpG oligonucleotides (see e.g. claim 63). According to the instant specification, CpG-motif oligonucleotides meet the limitations of the claims for a TLR9 agonist oligonucleotide (see e.g. instant specification page 3, line 1). According to Nallagatla, the shell can be comprised of combinations of different types of oligonucleotides, including a mixture of A-, B-, and C-class CpG oligonucleotides, which would meet the limitations for both the TLR9 agonist oligonucleotide, and the additional oligonucleotide in the nanoparticle shell as required by the instant claims (see e.g. claim 67, page 6, lines 15-25). The IS-SNA can comprise a liposomal core (see e.g. page 23, lines 20-34, claim 35, claim 59). The nanostructures of Nallagatla can be composed of nanoparticles having a core and a shell of oligonucleotides, which is formed by arranging CpG oligonucleotides such that they point radially outwards from the core (see e.g. page 22, lines 1-12). A hydrophobic (e.g. lipid) anchor group attached to either the 5' - or 3 '-end of the oligonucleotide, depending on whether the 5 oligonucleotides are arranged with the 5' - or 3 '-end facing outward from the core preferably is used to embed the oligonucleotides to a lipid based nanoparticle (see e.g. page 22, lines 1-12). The anchor acts to drive insertion into the lipid nanoparticle and to anchor the oligonucleotides to the lipids (see e.g. page 22, lines 1-12). The IS-SNA may be modified to include a cancer antigen (see e.g. page 26, lines 10-16). The IS-SNA can be designed to include peptides, proteins, or targeting antibodies along with the oligonucleotides on the nanoparticle, wherein the peptide or protein can be a cancer antigen (see e.g. page 26, lines 15-20; page 37, lines 1-10). The IS-SNA can be present in a pharmaceutical composition with a carrier and various excipients (see e.g. page 29, lines 14-30).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the copending application would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the copending application, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt and the lipid-anchored antigen of Nallagatla in the liposome because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the copending application is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt and Nallagatla provide an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt, Nallagatla and the copending application therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt and Nallagatla into the liposome of the copending application, one would achieve an enhanced immunotherapeutic for treating cancer.
The provisional rejection of claims 1, 3, 7, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-7, 9, 37, 48, 50, 71, 82, 84, 90-92, 105-106, 108, 113, and 118 of copending Application No. 18/862,866 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The copending claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core (see e.g. claim 1 and 2). The oligonucleotide shell comprises immunostimulatory oligonucleotide such as a TLR9 agonist (see e.g. claim 40-42). The shell can comprise combinations of antisense, RNA, or other molecules (see e.g. claims 37-38), and can comprise at least two oligonucleotides having different sequences (see e.g. claim 66). The oligonucleotide can comprise a CpG nucleotide sequence (see e.g. claim 39). The nanoparticle can be a liposome (see e.g. claim 9 and 12). One or more oligonucleotides are attached to the nanoparticle core through a lipid anchor group (see e.g. claim 14). The SNA can be in a composition with another therapeutic agent (see e.g. claims 48-49). The SNA can be present in an antigenic composition in a carrier, diluent, etc. (see e.g. claim 41). The copending claims further teach a method of treating a disorder with the SNA (see e.g. claim 90). The disorder can be cancer (see e.g. claim 91).
The copending application does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the copending application would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the copending application, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the copending application is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt provides an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt and the copending application therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt into the liposome of the copending application, one would achieve an enhanced immunotherapeutic for treating cancer.
The provisional rejection of claims 1, 3, 7, 9, 14, 18, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-7, 9, 37, 48, 50, 71, 82, 84, 90-92, 105-106, 108, 113, and 118 of copending Application No. 18/862,866 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Nallagatla et al (WO 2017/193084 A1; filed 5/5/17; published 11/9/17) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The copending claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core (see e.g. claim 1 and 2). The oligonucleotide shell comprises immunostimulatory oligonucleotide such as a TLR9 agonist (see e.g. claim 40-42). The shell can comprise combinations of antisense, RNA, or other molecules (see e.g. claims 37-38), and can comprise at least two oligonucleotides having different sequences (see e.g. claim 66). The oligonucleotide can comprise a CpG nucleotide sequence (see e.g. claim 39). The nanoparticle can be a liposome (see e.g. claim 9 and 12). One or more oligonucleotides are attached to the nanoparticle core through a lipid anchor group (see e.g. claim 14). The SNA can be in a composition with another therapeutic agent (see e.g. claims 48-49). The SNA can be present in an antigenic composition in a carrier, diluent, etc. (see e.g. claim 41). The copending claims further teach a method of treating a disorder with the SNA (see e.g. claim 90). The disorder can be cancer (see e.g. claim 91).
The copending application does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
The copending application and Bayyurt do not teach that the composition also includes a cancer antigen, or that the antigen is attached to the oligonucleotide in the shell through a lipid anchor.
Nallagatla teaches immunostimulatory spherical nucleic acids (IS-SNA) for the treatment of cancer (see e.g. abstract, claim 35 and 55). The immunostimulatory oligonucleotide in the IS-SNA can increase the ratio of T-effector cells to T-regulatory cells relative to a linear immunostimulatory oligonucleotide not bound to an IS-SNA (see e.g. claim 50). The IS-SNA can target a TLR9 receptor in a cell (see e.g. claim 52). The IS-SNA can comprise an oligonucleotide shell comprised of immunostimulatory oligonucleotides positioned on the exterior of the core in an amount effective to treat cancer (see e.g. claim 55). The immunostimulatory oligonucleotides can be CpG oligonucleotides (see e.g. claim 63). According to the instant specification, CpG-motif oligonucleotides meet the limitations of the claims for a TLR9 agonist oligonucleotide (see e.g. instant specification page 3, line 1). According to Nallagatla, the shell can be comprised of combinations of different types of oligonucleotides, including a mixture of A-, B-, and C-class CpG oligonucleotides, which would meet the limitations for both the TLR9 agonist oligonucleotide, and the additional oligonucleotide in the nanoparticle shell as required by the instant claims (see e.g. claim 67, page 6, lines 15-25). The IS-SNA can comprise a liposomal core (see e.g. page 23, lines 20-34, claim 35, claim 59). The nanostructures of Nallagatla can be composed of nanoparticles having a core and a shell of oligonucleotides, which is formed by arranging CpG oligonucleotides such that they point radially outwards from the core (see e.g. page 22, lines 1-12). A hydrophobic (e.g. lipid) anchor group attached to either the 5' - or 3 '-end of the oligonucleotide, depending on whether the 5 oligonucleotides are arranged with the 5' - or 3 '-end facing outward from the core preferably is used to embed the oligonucleotides to a lipid based nanoparticle (see e.g. page 22, lines 1-12). The anchor acts to drive insertion into the lipid nanoparticle and to anchor the oligonucleotides to the lipids (see e.g. page 22, lines 1-12). The IS-SNA may be modified to include a cancer antigen (see e.g. page 26, lines 10-16). The IS-SNA can be designed to include peptides, proteins, or targeting antibodies along with the oligonucleotides on the nanoparticle, wherein the peptide or protein can be a cancer antigen (see e.g. page 26, lines 15-20; page 37, lines 1-10). The IS-SNA can be present in a pharmaceutical composition with a carrier and various excipients (see e.g. page 29, lines 14-30).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the copending application would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the copending application, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt and the lipid-anchored antigen of Nallagatla in the liposome because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the copending application is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt and Nallagatla provide an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt, Nallagatla and the copending application therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt and Nallagatla into the liposome of the copending application, one would achieve an enhanced immunotherapeutic for treating cancer.
The provisional rejection of claims 1, 3, 7, 14, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 3-8, 13, 15, 17-19, 24, 27, 30, 33, 36, and 41-46 of copending Application No. 18/949,786 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The copending claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core, wherein the oligonucleotide shell comprises a mixture of Class A and Class B CpG Oligonucleotide (see e.g. claim 1 and 2). The SNA can further comprise an inhibitory oligonucleotide (see e.g. claim 18). The nanoparticle can be a liposome (see e.g. claim 19). The SNA can further comprise an additional agent such as a protein, peptide or small molecule (see e.g. claim 24). The copending claims further teach a method of treating a disorder with the SNA (see e.g. claim 41). The disorder can be cancer (see e.g. claim 42).
The copending application does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the copending application would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the copending application, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the copending application is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt provides an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt and the copending application therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt into the liposome of the copending application, one would achieve an enhanced immunotherapeutic for treating cancer.
The provisional rejection of claims 1, 3, 7, 9, 14, 18, 25, 29, and 42 on the ground of nonstatutory double patenting as being unpatentable over claims 3-8, 13, 15, 17-19, 24, 27, 30, 33, 36, 41-46 of copending Application No. 18/949,786 (reference application) in view of Bayyurt et al (Journal of Controlled Release 247 (2017) 134–144) and further in view of Nallagatla et al (WO 2017/193084 A1; filed 5/5/17; published 11/9/17) is maintained. The rejection of claim 28 is rendered moot by cancellation of the claim.
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core, one or more toll-like receptor 3 (TLR3) agonists encapsulated in the nanoparticle core and a shell of oligonucleotides comprising one or more toll like receptor 9 (TLR9) agonist oligonucleotides. The TLR3 agonist can be poly (I:C), the SNA further comprises an antigen wherein the antigen can be a peptide, protein, or cancer-related antigen such as tumor cell lysate. The antigen can be encapsulated in the nanoparticle core. The antigen can be attached to the surface of the nanoparticle core, the antigen is attached to an oligonucleotide in the shell of oligonucleotides or both. The antigen can be a prostate cancer antigen. The nanoparticle core can be a liposomal core. The TLR9 agonist oligonucleotide in the shell of oligonucleotides is attached to the external surface of the nanoparticle core through a lipid anchor group. The shell of oligonucleotides comprises one or more additional oligonucleotides. The SNA can further comprise one or more additional oligonucleotides encapsulated in the nanoparticle core. The additional oligonucleotides encapsulated in the nanoparticle core comprises mRNA, plasmid DNA, a therapeutic oligonucleotide, a detection oligonucleotide or a combination thereof. The claims are further directed to an antigenic composition comprising the SNA in a pharmaceutical composition with a carrier, diluent, stabilizer, preservative, or adjuvant, wherein the composition is capable of generating an immune response including antibody generation or a protective immune response in a mammalian subject.
The copending claims are directed to a spherical nucleic acid (SNA) comprising a nanoparticle core and an oligonucleotide shell attached to the external surface of the nanoparticle core, wherein the oligonucleotide shell comprises a mixture of Class A and Class B CpG Oligonucleotide (see e.g. claim 1 and 2). The SNA can further comprise an inhibitory oligonucleotide (see e.g. claim 18). The nanoparticle can be a liposome (see e.g. claim 19). The SNA can further comprise an additional agent such as a protein, peptide or small molecule (see e.g. claim 24). The copending claims further teach a method of treating a disorder with the SNA (see e.g. claim 41). The disorder can be cancer (see e.g. claim 42).
The copending application does not teach one or more TLR3 agonist encapsulated in the nanoparticle core, such as poly I:C, one or more additional oligonucleotides encapsulated in the nanoparticle core such as a therapeutic oligonucleotide.
Bayyurt teaches liposomal carrier system co-encapsulating poly I:C as a TLR agonist ligand and CpG ODN as a TLR9 agonist motif in a liposome (see e.g. abstract). Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. abstract). The co-encapsulated agonists showed slower tumor progression, and suggested that using liposomes with the co-encapsulated TLR3 and TLR9 agonists and a specific cancer antigen could be developed for a cancer vaccine.
The copending application and Bayyurt do not teach that the composition also includes a cancer antigen, or that the antigen is attached to the oligonucleotide in the shell through a lipid anchor.
Nallagatla teaches immunostimulatory spherical nucleic acids (IS-SNA) for the treatment of cancer (see e.g. abstract, claim 35 and 55). The immunostimulatory oligonucleotide in the IS-SNA can increase the ratio of T-effector cells to T-regulatory cells relative to a linear immunostimulatory oligonucleotide not bound to an IS-SNA (see e.g. claim 50). The IS-SNA can target a TLR9 receptor in a cell (see e.g. claim 52). The IS-SNA can comprise an oligonucleotide shell comprised of immunostimulatory oligonucleotides positioned on the exterior of the core in an amount effective to treat cancer (see e.g. claim 55). The immunostimulatory oligonucleotides can be CpG oligonucleotides (see e.g. claim 63). According to the instant specification, CpG-motif oligonucleotides meet the limitations of the claims for a TLR9 agonist oligonucleotide (see e.g. instant specification page 3, line 1). According to Nallagatla, the shell can be comprised of combinations of different types of oligonucleotides, including a mixture of A-, B-, and C-class CpG oligonucleotides, which would meet the limitations for both the TLR9 agonist oligonucleotide, and the additional oligonucleotide in the nanoparticle shell as required by the instant claims (see e.g. claim 67, page 6, lines 15-25). The IS-SNA can comprise a liposomal core (see e.g. page 23, lines 20-34, claim 35, claim 59). The nanostructures of Nallagatla can be composed of nanoparticles having a core and a shell of oligonucleotides, which is formed by arranging CpG oligonucleotides such that they point radially outwards from the core (see e.g. page 22, lines 1-12). A hydrophobic (e.g. lipid) anchor group attached to either the 5' - or 3 '-end of the oligonucleotide, depending on whether the 5 oligonucleotides are arranged with the 5' - or 3 '-end facing outward from the core preferably is used to embed the oligonucleotides to a lipid based nanoparticle (see e.g. page 22, lines 1-12). The anchor acts to drive insertion into the lipid nanoparticle and to anchor the oligonucleotides to the lipids (see e.g. page 22, lines 1-12). The IS-SNA may be modified to include a cancer antigen (see e.g. page 26, lines 10-16). The IS-SNA can be designed to include peptides, proteins, or targeting antibodies along with the oligonucleotides on the nanoparticle, wherein the peptide or protein can be a cancer antigen (see e.g. page 26, lines 15-20; page 37, lines 1-10). The IS-SNA can be present in a pharmaceutical composition with a carrier and various excipients (see e.g. page 29, lines 14-30).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt in the liposome core to increase innate immune activation upon administration. Bayyurt teaches that combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory (see e.g. Bayyurt abstract). Bayyurt revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells (see e.g. Bayyurt abstract). Synergistic immune activation elucidated in hPBMCs with liposomes co-encapsulating poly(I:C) and CpG ODN was synergistic (see e.g. Bayyurt page 139, right column). Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C) (see e.g. Bayyurt abstract). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection (see e.g. Bayyurt abstract). Bayyurt concluded that low doses of non-encapsulated single TLR ligand could be insufficient to mount an appreciable degree of immune activation. (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that liposomes act as a depot delivery system and improve cellular uptake of the ligands (see e.g. Bayyurt, page 142, left column). Uptake of CpG ODN is higher by immune cells when it is encapsulated within liposomes (SSCL) (see e.g. Bayyurt, page 142, left column). Bayyurt teaches that CpG ODN uptake was even higher when administered together with poly(I:C) into liposomes (see e.g. Bayyurt, page 142, left column). Dual uptake of ligands amplified sixfold more than non-encapsulated or separately encapsulated dual ligands (see e.g. Bayyurt, page 142, left column). It would be expected, absent evidence to the contrary, that co-encapsulating poly (I:C) and CpG ODN with the tumor lysate in the liposomes of the copending application would generate liposomes that have greater immune stimulating capabilities to treat cancer. The advantage of potential synergistic immune activation that has potential to have an increased antitumor effect for patients provides the motivation to make the aforementioned modification of the SNA of the copending application, based on the teachings of Bayyurt, with a reasonable expectation of success.
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to modify the SNA of the copending application to incorporate poly I:C and CpG ODN of Bayyurt and the lipid-anchored antigen of Nallagatla in the liposome because the Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The liposome of the copending application is an immunotherapeutic for cancer that uses a liposome core and TLR agonist to stimulate a patient’s immune system to treat cancer. Bayyurt and Nallagatla provide an analogous liposome product comprising agents that induce an increased immune response. The differences between Bayyurt, Nallagatla and the copending application therefore represent known variations of similar products that could be combined with known methods, which would render the combination predictable to one of ordinary skill in the art.
Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by incorporating the poly (I:C) of Bayyurt and Nallagatla into the liposome of the copending application, one would achieve an enhanced immunotherapeutic for treating cancer.
Applicant’s Arguments
Applicant argues:
1. Applicant argues that Nallagatla is silent regarding TLR3 agonists encapsulated within the nanoparticle core, and points to Nallagatla describing that the nanostructures are typically composed of nanoparticles having a core and a shell of oligonucleotides. These disclosures do not suggest encapsulating TLR3 agonists within the core structure, and Applicant asserts that there is no disclosure in Nallagatla suggesting encapsulation of any substance.
Further, Bayyurt requires that both TLR ligands are co-encapsulated within a liposome, which is fundamentally different from the claimed structure of the instant claims, where one or more TLR3 agonists are encapsulated in a nanoparticle core, while one or more TLR9 agonist oligonucleotides form the external shell. Bayyurts approach involves having both ligands co-encapsulated to achieve simultaneous delivery to innate immune cells. Such a combination would not suggest the SNA recited in the instant claims, because Nallagatla’s architecture is specifically designed for surface presentation of immunostimulatory oligonucleotides.
2. The nanoparticles of the instant claims target activation of different TLR pathways that are not disclosed or suggested by the combination of the cited documents.
Applicant’s arguments have been fully considered and are not persuasive for the following reasons:
1. Applicant is attempting to argue the limitations of the references individually, without addressing the combined teachings. As stated in MPEP 2145, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Nallagatla specifically provides for the same type of structure as Bayyurt, including liposomes (see e.g. claim 5 of Nallagatla), and specifically describes encapsulating substances (see e.g. page 29, line 30). The instant specification identifies liposomes as an appropriate nanoparticle (for example, see e.g. instant specification paragraphs [0015]-[0016]). Bayyurt provides evidence of the specific type of compounds that should be combined in the core of the nanoparticle, which can also be a liposome, similar to Nallagatla, to achieve maximum therapeutic effect.
Applicant is reminded that the instant claims recite the transitional phrase “comprising” which is open-ended and allows for additional substances to be attached or encompassed by the claimed SNA. This term “comprising” specifically encompasses all types of additional substances in the SNA, including those not specifically claimed, and this includes the possibility that multiple substances could be present in the core. The claims further explicitly do not exclude any specific additional substances. The two-agent core of Bayyurt would therefore be encompassed by the instant claims. Furthermore, the existence of Bayyurt’s core does not require disruption of the structure of Nallagatla’s particles. Applicant has failed to acknowledged that both Nallagatla’s surface presentation architecture, AND Bayyurt’s core could be present as described. There is no limitation either in the instant claims or in Nallagatla that would exclude multiple molecules from being present in the particle core.
2. Applicant is arguing limitations that are not claimed. The instant claims do not recite a requirement to activate a specific pathway. According to MPEP 2145, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993)
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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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
/BRIAN GANGLE/Primary Examiner, Art Unit 1645