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 .
Detailed Action
This action is in response to the papers filed December 30, 2025.
Amendments
Applicant's response, filed December 30, 2025, is acknowledged. Applicant has cancelled Claims 2-3 and 5, withdrawn Claims 7-11, 14, 18, and 20-31, and amended Claims 1, 4, 6, 12-13, 15-17, and 19.
Claims 1, 4, and 6-31 are pending.
Election/Restrictions
Applicant has elected with traverse the following species:
i) the alternative CD38 inhibitor species is 78C, as recited in Claims 4 and 26;
ii) the alternative targeting moiety species is an antibody that targets CD14, as recited in Claims 5 and 23;
iii) the alternative target tissue/organ species is liver, as recited in Claims 13 and 17;
iv) the alternative method step species is ex vivo organ perfusion, as recited in Claims 15 and 19; and
v) the alternative disease species is inflammatory liver disease, as recited in Claims 8 and 27.
In light of the cited art below, the Examiner withdrew the species election (i) directed to alternative CD38 inhibitors.
Claims 1, 4, and 6-31 are pending.
Claims 7-11, 14, 18, and 20-31 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 4, 6, 12-13, 15-17, and 19 are under consideration.
Priority
This application is a 371 of PCT/US2020/059343 filed on November 6, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/932,152, filed on November 7, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Objections
1. Claim 1 is objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
The first (lines 2-3) and second (lines 4-6) ‘; wherein’ clauses should be separated by line indentation.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
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.
2. The prior rejection of Claims 1-6, 12-13, 15-17, and 19 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to the claims replacing “nanovesicle” with “nanoparticle”, which the Examiner finds persuasive.
3. The prior rejections of Claims 3-4, 13, and 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of Applicant’s amendment to the claims replacing “comprising” with “is”, which the Examiner finds persuasive.
4. The prior rejections of Claims 3-4, 13, and 17 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, are withdrawn in light of Applicant’s amendment to the claims replacing “comprising” with “is”, which the Examiner finds persuasive.
5. Claims 1, 4, 6, 12-13, 15-17, and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, Applicant has amended Claim 1 to recite the broad recitation "small molecule comprises", and the claim also recites a list of compounds, which is/are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The recitation "comprises" is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and docs not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). The breadth of the claims continues to encompass a genus of unrecited elements, and the specification discloses that the positively recited elements are embodiments of the subgenera already recited in the claim.
The Examiner suggests replacing “comprises” with “is”, as discussed in the prior Office Action.
The Examiner notes that the instant specification fails to provide support for a small molecule [structure 1] comprising a thiazoloquin(as)olin(on)e compound [structure 2], for example. Rather, the small molecule is a thiazoloquin(as)olin(on)e compound. See, for example, Example 5, the small molecule is 78C.
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
6. Claim(s) 1, 4, 6, 12-13, 15-17, and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has amended Claim 1 to recite the broad recitation "small molecule comprises", and the claim also recites a list of compounds, which is/are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The recitation "comprises" is open-ended and allows for additional, unrecited elements in the claims. MPEP 2111.03 specifically sets forth that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and docs not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). The breadth of the claims continues to encompass a genus of unrecited elements, and the specification discloses that the positively recited elements are embodiments of the subgenera already recited in the claim.
The Examiner suggests replacing “comprises” with “is”, as discussed in the prior Office Action.
The Examiner notes that the instant specification fails to provide support for a small molecule [structure 1] comprising a thiazoloquin(as)olin(on)e compound [structure 2], for example. Rather, the small molecule is a thiazoloquin(as)olin(on)e compound. See, for example, Example 5, the small molecule is 78C.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
7. Claim(s) 1, 4, 6, 12-13, 15-17, and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites an engineered nanovesicle comprising a targeting moiety and an inhibitor of CD38,
wherein the targeting moiety targets endothelium or macrophage contained in interstitial compartments of a tissue or organ of interest.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
There is a lack of adequate written description regarding the structure/function nexus of:
the enormous genus of structurally and functionally undisclosed targeting moieties recited at a high level of generality; and
the enormous genus of structurally and functionally undisclosed CD38 inhibitors recited at a high level of generality.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The breadth of the claims encompass an enormously vast genus of structurally and functionally undisclosed targeting moieties recited at a high level of generality, whereby the targeting moiety may be a peptide, polypeptide, antibody, lipid, carbohydrate, oligonucleotide, aptamer, or small molecule, said targeting moiety(ies) having the functional property of targeting and/or binding to an essentially infinite genus of structurally undisclosed target small molecules, chemical compounds, fatty acids, carbohydrates, nucleic acids, amino acid peptides and/or polypeptides present in and/or expressed by endothelium or macrophages, including, but not limited to, CD14.
Rich et al (U.S. 2017/0165376) is considered relevant art for having disclosed aptamers being 200, 100, 50, 40, or 35 nucleotides in length (e.g. [0030]).
Doyle et al (U.S. Patent 8,105,982) is considered relevant prior art for having disclosed aptamers being 20-50 nucleotides in length (e.g. col. 4, lines 13-14), whereby the aptamers may have an enormous range of binding affinities to its corresponding target molecule, ranging from as low as 10^-4 M, 10^-5 M, 10^-6M, 10^-8M, or 10^-9M (col. 12, lines 5-7; col 14, lines 1-2), a range of at least 5 orders of magnitude.
4^200 = about 2x10^120 structurally undisclosed aptamers or other nucleic acid molecules.
4^150 = about 2x10^90 structurally undisclosed aptamers or other nucleic acid molecules.
4^100 = about 1x10^60 structurally undisclosed aptamers or other nucleic acid molecules.
4^75 = about 1x10^45 structurally undisclosed aptamers, other nucleic acid molecules, or oligonucleotides.
4^50 = about 1x10^30 structurally undisclosed aptamers, other nucleic acid molecules, or oligonucleotides.
4^30 = about 1x10^18 structurally undisclosed aptamers, other nucleic acid molecules, or oligonucleotides.
(www.calculator.net/exponent-calculator; last visited June 11, 2025)
Thus, the claims encompass an enormously vast genus of about 2x10^120, 2x10^90, 1x10^60, 1x10^45, 1x10^30, and/or 1x10^18 structurally undisclosed aptamer, nucleic acid, or oligonucleotide sequences that are to have the functional property of binding to an essentially infinite genus of structurally undisclosed target small molecules, chemical compounds, fatty acids, carbohydrates, nucleic acids, amino acid peptides and/or polypeptides present in and/or expressed by endothelium or macrophages, including, but not limited to, CD14.
Cho et al (Quantitative selection and parallel characterization of aptamers, PNAS 110(46): 18460-18465, 2013) is considered relevant prior art for having taught that, while aptamers with high affinity and specificity have been previously reported for a wide range of molecular targets, including proteins, and that recent advances in selection and sequencing techniques have greatly increased the efficiency of aptamer discovery, despite these advances, the generation of high-quality aptamers remains a time-consuming and low-throughput process (pg 18460, Introduction). Screening a library of 10^14 molecules (pg 18464, col. 1, Methods) yielded only about 235 initial candidate aptamers, of which only 8 possessed sufficient high affinity to their target (e.g. Figure 3).
Tiessen et al (Mathematical modeling and comparison of protein size distribution in different plant, animal, fungal and microbial species reveals a negative correlation between protein size and protein number, thus providing insight into the evolution of proteomes, BMC Research Notes 5(85): 23 pages, doi:10.1186/1756-0500-5-85, 2012) is considered relevant prior art for having taught that the average eukaryotic protein is about 472 amino acids in length (Abstract).
20^470 = an infinite genus of structurally undisclosed amino acid sequences.
20^425 = an infinite genus of structurally undisclosed amino acid sequences.
20^375 = an infinite genus of structurally undisclosed amino acid sequences.
20^325 = an infinite genus of structurally undisclosed amino acid sequences.
20^275 = an infinite genus of structurally undisclosed amino acid sequences.
20^225 = about 5x10^292 structurally undisclosed amino acid sequences.
20^175 = about 5x10^227 structurally undisclosed amino acid sequences.
20^125 = about 4x10^162 structurally undisclosed amino acid sequences.
20^75 = about 4x10^97 structurally undisclosed amino acid sequences.
20^25 = about 3x10^32 structurally undisclosed amino acid sequences.
(www.calculator.net/exponent-calculator; last visited June 11, 2025)
Thus, the breadth of the claims reasonably encompasses an infinite and/or an enormously vast genus of about 5x10^292, 5x10^227, 4x10^162, 4x10^97, and/or 3x10^32 structurally and functionally undisclosed peptides, polypeptides, and antibodies that are to have the functional property of binding to an essentially infinite genus of structurally undisclosed target small molecules, chemical compounds, fatty acids, carbohydrates, nucleic acids, amino acid peptides and/or polypeptides present in and/or expressed by endothelium or macrophages, including, but not limited to, CD14.
Given the highly diverse structural nature of antibodies, particularly in the CDRs, one of ordinary skill in the art generally cannot envision the structure of an antibody by knowing its binding characteristics.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of a given antibody. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain the required conformation of the CDRs are required in order to produce a protein having antigen-binding function; and further, that proper association of heavy and light chain variable regions is required in order to form functional binding sites.
MacCallum et al. (Antibody-antigen Interactions: Contact Analysis and Binding Site Topography, J. Mol. Biol. 262:732-745, 1996) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (pg 733, col. 2) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (pg 735, col. 1).
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al (A peptide mimetic of an anti-CD4 monoclonal antibody by rational design, Biochem. Biophys. Res. Comm. 307:198-205, 2003), who constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (pg 199, col. 1). Thus, while one can make the statement that CDRs from a single antibody chain make a significant contribution in the antigen binding, the CDR domains from a single chain are not the only residues that influence binding, and in fact the prior art does not support that CDR domains from a single chain alone are sufficient to define the binding specificity of an antibody.
Goel et al (Plasticity within the Antigen-Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response, J. Immunol. 173: 7358-7367, 2004) taught the generation of monoclonal antibodies directed to the same antigen, whereby three antibodies that bind to the same 12-mer epitope/antigen have substantial amino acid diversity in the CDRs (Figure 3) and binding kinetics (Table III, Figure 6).
Poosarla et al (Computational De Novo Design of Antibodies Binding to a Peptide With High Affinity, Biotech. & Bioengin. 114(6): 1331-1342, 2017) designed scFv fragments that bind to the same 12-mer epitope/antigen, and demonstrate substantial diversity in said antibody amino acid sequences (Figure 3). It appears that even though all antibodies bind to the same 12-mer they bind to different epitopes within it.
Edwards et al (The Remarkable Flexibility of the Human Antibody Repertoire; Isolation of Over One Thousand Different Antibodies to a Single Protein, BLyS, J. Mol. Biol. 334: 103-118, 2003) taught the ability to identify over 1000 antibodies composed of structurally different amino acid sequences that bind to a single antigen (see entire paper).
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of about 1x10^208, 1x10^139, 9x10^68, 1x10^35, 6x10^20, and/or 2x10^14 structurally and functionally undisclosed variants of SEQ ID NO:4 to bind to their enormously vast genus of structurally undisclosed first and second target antigens, respectively.
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered claimed targeting moieties and:
the enormously vast genus of about 2x10^120, 2x10^90, 1x10^60, 1x10^45, 1x10^30, and/or 1x10^18 structurally undisclosed aptamer, nucleic acid, or oligonucleotide sequences;
the essentially infinite genus of structurally undisclosed lipids, carbohydrates, and small molecules; and
the essentially infinite and/or an enormously vast genus of about 5x10^292, 5x10^227, 4x10^162, 4x10^97, and/or 3x10^32 structurally and functionally undisclosed peptides, polypeptides, and antibodies,
that are to necessarily and predictably have the functional properties of binding an essentially infinite genus of structurally undisclosed target small molecules, chemical compounds, fatty acids, carbohydrates, nucleic acids, amino acid peptides and/or polypeptides present in and/or expressed by endothelium or macrophages, including, but not limited to, CD14, respectively, is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to discover for themselves that which Applicant has failed to disclose.
Similarly, the breadth of the claims reasonably encompasses:
an enormously vast genus of about 2x10^120, 2x10^90, 1x10^60, 1x10^45, 1x10^30, and/or 1x10^18 structurally undisclosed aptamer, nucleic acid, or oligonucleotide sequences;
an essentially infinite genus of structurally undisclosed lipids, carbohydrates, and small molecules; and
an essentially infinite and/or an enormously vast genus of about 5x10^292, 5x10^227, 4x10^162, 4x10^97, and/or 3x10^32 structurally and functionally undisclosed peptides, polypeptides, and antibodies, that are to have the functional property of inhibiting CD38.
Toulorge et al (WO 19/020643; priority to July 24, 2017; of record in IDS) is considered relevant prior art for having disclosed that inhibition of CD38 leads to increased NAD+ levels, and conceived of compounds that bind CD38, e.g. antibodies, small molecules, oligonucleotides, and recombinant proteins (e.g. pg 9), thereby activating the opening of NAADP receptors TPC1 and/or TPC2, not by increasing NAD+ levels, as suggested by the literature (pg 3). However, Toulorge et al fails to demonstrate, for example, the hypothetical small molecules (e.g. pgs 29-55) actually inhibit CD38, nor any oligonucleotides or recombinant proteins. At best, Toulorge et al reduces to practice five anti-CD38 antibodies (e.g. pg 82, line 10).
Boslett et al (Inhibition of CD38 with the Thiazoloquin(az)olin(on)e 78c Protects the Heart against Postischemic Injury, J. Pharmacol. And Exp. Therapeutics 369: 55-64, doi.org/10.1124/jpet.118.254557; available online April 2019; of record in IDS) is considered relevant prior art for having taught that there had been a lack of potent CD38 inhibitors in the prior art, until a new class of thiazoloquin(az)olin(on)e compounds were identified (e.g. Abstract).
The gap between the number of as-yet to be discovered claimed CD38 inhibitors and:
the enormously vast genus of about 2x10^120, 2x10^90, 1x10^60, 1x10^45, 1x10^30, and/or 1x10^18 structurally undisclosed aptamer, nucleic acid, or oligonucleotide sequences;
the essentially infinite genus of structurally undisclosed lipids, carbohydrates, and small molecules; and
the essentially infinite and/or an enormously vast genus of about 5x10^292, 5x10^227, 4x10^162, 4x10^97, and/or 3x10^32 structurally and functionally undisclosed peptides, polypeptides, and antibodies,
that are to necessarily and predictably have the functional properties of inhibiting CD38, directly or indirectly, respectively, is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to discover for themselves that which Applicant has failed to disclose.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species 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 invention.
At best, the specification’s working example is directed to the thiazoloquin(az)olin(on)e compound, 78C.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial CD38 inhibitor is the thiazoloquin(az)olin(on)e compound, 78C, does not tell you anything at all about the structures of:
the enormously vast genus of about 2x10^120, 2x10^90, 1x10^60, 1x10^45, 1x10^30, and/or 1x10^18 structurally undisclosed aptamer, nucleic acid, or oligonucleotide sequences;
the essentially infinite genus of structurally undisclosed lipids, carbohydrates, and small molecules; and
the essentially infinite and/or an enormously vast genus of about 5x10^292, 5x10^227, 4x10^162, 4x10^97, and/or 3x10^32 structurally and functionally undisclosed peptides, polypeptides, and antibodies,
that are to necessarily and predictably have the functional properties of inhibiting CD38, directly or indirectly.
Similarly, knowing that the targeting moiety is to have the functional property of binding an essentially infinite genus of structurally undisclosed target small molecules, chemical compounds, fatty acids, carbohydrates, nucleic acids, amino acid peptides and/or polypeptides present in and/or expressed by endothelium or macrophages, including, but not limited to, CD14, does not tell you anything at all about the structures of:
the enormously vast genus of about 2x10^120, 2x10^90, 1x10^60, 1x10^45, 1x10^30, and/or 1x10^18 structurally undisclosed aptamer, nucleic acid, or oligonucleotide sequences;
the essentially infinite genus of structurally undisclosed lipids, carbohydrates, and small molecules; and
the essentially infinite and/or an enormously vast genus of about 5x10^292, 5x10^227, 4x10^162, 4x10^97, and/or 3x10^32 structurally and functionally undisclosed peptides, polypeptides, and antibodies,
that are to necessarily and predictably have the functional properties of binding an essentially infinite genus of structurally undisclosed target small molecules, chemical compounds, fatty acids, carbohydrates, nucleic acids, amino acid peptides and/or polypeptides present in and/or expressed by endothelium or macrophages, including, but not limited to, CD14.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
an enormously vast genus of about 2x10^120, 2x10^90, 1x10^60, 1x10^45, 1x10^30, and/or 1x10^18 structurally undisclosed aptamer, nucleic acid, or oligonucleotide sequences;
the essentially infinite genus of structurally undisclosed lipids, carbohydrates, and small molecules; and
the essentially infinite and/or an enormously vast genus of about 5x10^292, 5x10^227, 4x10^162, 4x10^97, and/or 3x10^32 structurally and functionally undisclosed peptides, polypeptides, and antibodies,
that are to have the functional properties of binding an essentially infinite genus of structurally undisclosed target small molecules, chemical compounds, fatty acids, carbohydrates, nucleic acids, amino acid peptides and/or polypeptides present in and/or expressed by endothelium or macrophages, including, but not limited to, CD14, or inhibit CD38.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant’s working examples are directed to the use of CD38 inhibitor 78C (e.g. Example 5).
Applicant prophetically conceives of, but does not reduce to practice, using an antibody that targets CD14 as a polymeric nanoparticle targeting moiety.
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of:
the enormously vast genus of structurally and functionally undisclosed targeting moieties recited at a high level of generality; and
the enormously vast genus of structurally and functionally undisclosed CD38 inhibitors recited at a high level of generality.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant argues that cancellation of Claims 2-3 and 5 render the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant has simply moved those limitations into amended Claim 1, which does not overcome the substantive issues of the enormously vast genus of about 2x10^120, 2x10^90, 1x10^60, 1x10^45, 1x10^30, and/or 1x10^18 structurally undisclosed aptamer, nucleic acid, or oligonucleotide sequences;
the essentially infinite genus of structurally undisclosed lipids, carbohydrates, and small molecules; and
the essentially infinite and/or an enormously vast genus of about 5x10^292, 5x10^227, 4x10^162, 4x10^97, and/or 3x10^32 structurally and functionally undisclosed peptides, polypeptides, and antibodies,
that are to have the functional properties of binding an essentially infinite genus of structurally undisclosed target small molecules, chemical compounds, fatty acids, carbohydrates, nucleic acids, amino acid peptides and/or polypeptides present in and/or expressed by endothelium or macrophages, including, but not limited to, CD14, or inhibit CD38.
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
8. The prior rejection of Claims 1-2 and 5-6 under AIA 35 U.S.C. 103 as being unpatentable over Kumara et al (2014; of record) in view of De La Puente et al (December 2, 2016; of record), Lokhorst et al (September 24, 2015; of record), Amici et al (available online July 9, 2018; of record), Goodrich et al (U.S. Patent 6,153,113; of record), and Johnsen et al (available online May 24, 2018; of record) is withdrawn in light of Applicant’s amendment to Claim 1 and cancellation of Claims 2-3, changing the scope of the CD38 inhibitor to an RNAi, oligonucleotide, or small molecule such as thiazoloquin(az)olin(on)e compounds, apigenin, kuromanin, or luteolinidin, limitations that the cited prior art do not teach/disclose.
9. The prior rejection of Claims 12-13, 15-17, and 19 under AIA 35 U.S.C. 103 as being unpatentable over Thijssen et al (available January 2019; of record) in view of Lam et al (available online September 4, 2019; of record), Tajima et al (available online September 19, 2019; of record), Kumara et al (2014; of record), De La Puente et al (2016; of record), Lokhorst et al (2015; of record), Amici et al (available online July 9, 2018; of record), Goodrich et al (of record), and Johnsen et al (available online May 24, 2018; of record) is withdrawn for reasons discussed above.
10. Claims 1 and 6 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Kumara et al (2014; of record) in view of Bhattacharya et al (available online May 23, 2018; of record) and Lam et al (available online September 4, 2019; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Kumara et al is considered relevant prior art for having taught an engineered polymeric nanoparticle comprising anti-CD14 antibodies as a targeting moiety and an encapsulated therapeutic drug (e.g. Title; pg 86, col. 2, Methods), thereby targeting the therapeutic nanoparticle to macrophages (e.g. pg 89, col. 2, “It is well targeted to macrophages”).
Kumara et al do not teach wherein the anti-CD14 polymeric nanoparticle further comprises a CD38 inhibitor molecule, e.g. apigenin.
However, prior to the effective filing date of the instantly claimed invention, Bhattacharya et al is considered relevant prior art for having taught engineered nanoparticles comprising apigenin, an art-recognized CD38 inhibitor, whereby said nanoparticles are taken up by liver cells (Title; entire paper).
Lam et al is considered relevant prior art for having taught that CD38 and CD14 are naturally expressed on macrophages, including macrophages in diseased liver tissue.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first therapeutic agent, as taught by Kumara et al, with a second therapeutic agent, i.e. apigenin, an art-recognized CD38 inhibitor, in a nanoparticle comprising anti-CD14 antibodies as a targeting moiety to macrophages, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first therapeutic agent with a second therapeutic agent, i.e. apigenin, an art-recognized CD38 inhibitor, in a nanoparticle comprising anti-CD14 antibodies as a targeting moiety to macrophages because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) anti-CD14 targets macrophages (Kumara et al), including liver macrophages (Lam et al); and
ii) CD38 inhibitors such as apigenin had already been successfully reduced to practice of being encapsulated in a nanoparticle for delivery to liver tissue (Bhattacharya et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 6, Kumara et al taught a pharmaceutical composition comprising the engineered nanoparticles (e.g. pg 86, col. 2, e.g. NPs in ultrapure water).
Bhattacharya et al taught a pharmaceutical composition comprising the engineered nanoparticles (e.g. Title; pg 1907, col. 2, Methods, “hepatocarcinogenesis model, treatment schedule, intravenous dose”).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that Kumara et al do not teach an inhibitor of intracellular CD38.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Bhattacharya et al is considered relevant prior art for having taught engineered nanoparticles comprising apigenin, an art-recognized CD38 inhibitor, whereby said nanoparticles are taken up by liver cells (Title; entire paper).
Lam et al is considered relevant prior art for having taught that CD38 and CD14 are naturally expressed on macrophages, including macrophages in diseased liver tissue.
Applicant argues that the Examiner has not explained why the ordinary artisan would exchange the anti-CD14 antibody of Kumara et al with a CD38 inhibitor.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner has not set forth such a substitution. Rather, it would have been obvious to one of ordinary skill in the art to substitute a first therapeutic agent, as taught by Kumara et al, with a second therapeutic agent, i.e. apigenin, an art-recognized CD38 inhibitor, in a nanoparticle comprising anti-CD14 antibodies as a targeting moiety to macrophages, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).”
11. Claim(s) 4 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Kumara et al (2014; of record) in view of Bhattacharya et al (available online May 23, 2018; of record) and Lam et al (available online September 4, 2019; of record), as applied to Claims 1 and 6 above, and in further view of Haffner et al (April 1, 2015; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Neither Kumara et al, Bhattacharya et al, nor Lam et al teach wherein the CD38 inhibitor molecule is a thiazoloquin(az)olin(on)e molecule, more specifically, 78C.
However, prior to the effective filing date of the instantly claimed invention, Haffner et al is considered relevant prior art for having taught the discovery and synthesis of thiazoloquin(az)olin(on)e CD38 inhibitors, including, more specifically, 78C.
Haffner et al taught that:
i) the thiazoloquin(az)olin(on)e CD38 inhibitors, including, more specifically, 78C, possessed the most potent CD38 inhibitory activity of any small molecules described in the literature to date (Abstract);
ii) 78C had better clearance values, a higher volume of steady state distribution, and a longer half-life in vivo, and thus on the basis of its overall pharmacokinetic profile, was selected for in in vivo studies (e.g. pg 3556, col. 2); and
iii) 78C should provide a valuable tool for CD38-mediated pharmacology (e.g. pg 3556, col. 2).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first CD38 inhibitor, e.g. apigenin, as taught by Bhattacharya et al, with a second CD38 inhibitor, i.e. 78C, as taught by Haffner et al, in a nanoparticle comprising anti-CD14 antibodies as a targeting moiety to macrophages, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first CD38 inhibitor, e.g. apigenin, with a second CD38 inhibitor, i.e. 78C, in a nanoparticle comprising anti-CD14 antibodies as a targeting moiety to macrophages because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) anti-CD14 targets macrophages (Kumara et al), including liver macrophages (Lam et al); and
ii) CD38 inhibitors such as apigenin had already been successfully reduced to practice of being encapsulated in a nanoparticle for delivery to liver tissue (Bhattacharya et al); and
iii) Haffner et al taught that 78C possessed the most potent CD38 inhibitory activity of any small molecules described in the literature to date, has better clearance values, a higher volume of steady state distribution, and a longer half-life in vivo, as compared to other thiazoloquin(az)olin(on)e molecules, and should provide a valuable tool for CD38-mediated pharmacology.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant iterates prior arguments, as applied to 78C.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner has responded prior arguments above.
12. Claims 12-13, 15-17, and 19 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Thijssen et al (available January 2019; of record) in view of Lam et al (available online September 4, 2019; of record), Tajima et al (available online September 19, 2019; of record), Kumara et al (2014; of record), Bhattacharya et al (available online May 23, 2018; of record), Haffner et al (April 1, 2015; of record), Chen et al (2001; of record), Mukherjee et al (2017; of record), and Boslett et al (available online April 2019; of record in IDS).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 12-13, 15-17, and 19, Thijssen et al is considered relevant prior art for having taught a method of preparing a liver for transplant, the method comprising the step of contacting the liver by ex vivo perfusion with a therapeutic liposome (e.g. pg 148, col. 1, “encapsulating siRNA in lipid-based nanoparticles”, thereby inhibiting, reducing, or repairing tissue damage to the liver during a transplantation procedure.
Thijssen et al taught that ex vivo perfusion procedure has several advantages, including more efficient delivery, lower doses and cost-savings, and none or fewer side-effects to other organs, whereby ex vivo delivery by machine perfusion may be especially beneficial for improving the viability of extended criteria donor (ECD) organs by alleviating ischemia/reperfusion injury (IRI), improve graft tolerance, and can improve target-cell specificity in a clinically more achievable administration platform, (e.g. Abstract; pg 149, col. 2).
Thijssen et al do not teach the therapeutic nanoparticle is a nanoparticle comprising anti-CD14 and a CD38 inhibitor.
However, prior to the effective filing date of the instantly claimed invention, Lam et al is considered relevant prior art for having taught that CD38 and CD14 are naturally expressed on macrophages, including macrophages in diseased liver tissue.
Tajima et al is considered relevant prior art for having taught that a CD38 inhibitor, to wit, daratumumab, an anti-CD38 antibody, is a promising candidate to diminish activated plasma cells and to minimize antibody-mediated rejection (e.g. pg 4, col. 1) after organ transplantation, whereby said organ is liver (e.g. Title, Abstract).
As discussed above, Kumara et al, Bhattacharya et al, and Haffner et al render a nanoparticle comprising anti-CD14 and a CD38 inhibitor, i.e. apigenin or thiazoloquin(az)olin(on)e molecules, i.e. 78C, prima facie obvious.
Haffner et al taught that 78C possessed the most potent CD38 inhibitory activity of any small molecules described in the literature to date, has better clearance values, a higher volume of steady state distribution, and a longer half-life in vivo, as compared to other thiazoloquin(az)olin(on)e molecules, and should provide a valuable tool for CD38-mediated pharmacology, having been demonstrated to elevate nicotinamide adenine dinucleotide (NAD) levels in vivo (e.g. pg 3556, col. 2).
Chen et al is considered relevant prior art for having taught a method of inhibiting, reducing, or repairing tissue damage in a liver, e.g. ischemia/reperfusion injury, the method comprising the step of administering to the liver nacinamide (e.g. pg 450, col. 2, “the protective effect of niacinamide on I/R-induced liver injury”). Chen et al taught that PARS activity results in the rapid depletion of intracellular nicotinamide adenine dinucleotides and ATP, eventually inducing irreversible cytotoxicity; whereas, niacinamide inhibits PARS, thereby attenuating I/R-induced liver injury (e.g. Abstract). Chen et al taught that nicotinamide is a precursor of NAD+, which increases hepatocyte ATP concentration and protects against reperfusion injury by reducing oxidative and nitrosative toxicity (e.g. pg 451, col. 1).
Mukherjee et al is considered relevant prior art for having taught a method of inhibiting, reducing, or repairing tissue damage in a liver, e.g. hepatectomy, the method comprising the step of administering to the liver nicotinamide riboside (NR), a precursor for nicotinamide adenine dinucleotide (NAD) biosynthesis (e.g. Abstract). Mukherjee et al that nicotinamide adenine dinucleotide (NAD) biosynthesis promotes liver regeneration (Title), and that increasing NAD levels resulted in enhanced liver regeneration (Abstract; pg 622, col. 2).
Boslett et al is considered relevant prior art for having taught that the CD38 inhibitor thiazoloquin(az)olin(on)e 78C has favorable tissue uptake and marked protective effects against I/R injury (e.g. Abstract).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first therapeutic nanoparticle, as taught by Thijssen et al, with a second therapeutic nanoparticle, i.e. a nanoparticle comprising anti-CD14 and a CD38 inhibitor, i.e. apigenin or thiazoloquin(az)olin(on)e molecules, i.e. 78C, in a method of preparing a liver for transplant, the method comprising the step of contacting the liver by ex vivo perfusion with a therapeutic nanoparticle, thereby inhibiting, reducing, or repairing tissue damage to the liver during a transplantation procedure, with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first therapeutic nanoparticle with a second therapeutic nanoparticle, i.e. a nanoparticle comprising anti-CD14 and a CD38 inhibitor, i.e. apigenin or thiazoloquin(az)olin(on)e molecules, i.e. 78C, in a method of preparing a liver for transplant, the method comprising the step of contacting the liver by ex vivo perfusion with a therapeutic nanoparticle, thereby inhibiting, reducing, or repairing tissue damage to the liver during a transplantation procedure, because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) anti-CD14 targets macrophages (Kumara et al), including liver macrophages (Lam et al); and
ii) CD38 inhibitors are a promising candidate to diminish activated plasma cells and to minimize antibody-mediated rejection after organ transplantation, whereby said organ is liver (Tajima et al);
iii) CD38 inhibitors had already been successfully reduced to practice being delivered to liver tissue via nanoparticles (Bhattacharya et al);
iii) Haffner et al taught that 78C possessed the most potent CD38 inhibitory activity of any small molecules described in the literature to date, has better clearance values, a higher volume of steady state distribution, and a longer half-life in vivo, as compared to other thiazoloquin(az)olin(on)e molecules, and should provide a valuable tool for CD38-mediated pharmacology, having been demonstrated to elevate NAD levels in vivo (e.g. pg 3556, col. 2);
iv) elevated nicotinamide adenine dinucleotide (NAD) levels, as would be achieved per CD38 inhibitors (Tajima et al; Haffner et al), promotes liver regeneration and is protective against or attenuates ischemia/reperfusion injury, as it increases hepatocyte ATP levels, reduces oxidative and nitrosative toxicity (Chen et al; Mukherjee et al); and
v) the CD38 inhibitor thiazoloquin(az)olin(on)e 78C has favorable tissue uptake and marked protective effects against I/R injury (Boslett et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
Response to Arguments
Applicant iterates prior arguments.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner has responded prior arguments above.
Conclusion
13. No claims are 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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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638