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 .
Status of the Claims
Claims 1-26 and 32-55 are pending in this application. Claims 27-31 have been cancelled by Applicant. Claims 1-21, 32, and 40-55 are under examination herein. Claims 22-26 and 33-39 are withdrawn from consideration.
Claim Rejections - 35 USC § 103
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.
Claims 1-8, 21, and 40-43 are rejected under 35 U.S.C. 103 as being unpatentable over Mura et al. (Journal of Controlled Release, 208, 2015, 25–41 – previously cited) (“Mura”); in view of Jo et al. (US 6,703,417 B2 – previously cited) (“Jo”); further in view of Zaro et al. (The AAPS Journal, 17, 2015, 83-92 – previously cited) (“Zaro”).
Regarding claims 1 and 40-41, Mura discloses lipid prodrug nanocarriers in cancer therapy. Mura teaches Lipids have been widely used as building blocks for the design of various prodrugs due to their ability to self-assemble and/or to be incorporated into lipid/polymer matrices, allowing drugs to be delivered through a nanoparticulate form (abstract). Mura teaches that among the different classes of drug conjugates in prodrugs, lipids (fatty acids, cholesterols, phospholipids, triglycerides, etc.) represent materials of choice due to their biocompatibility, low toxicity, and ability to be cleared from the body (page 26, col. 1, para. 2, lines 5-13).
Mura discloses a series of paclitaxel (PTX) prodrugs conjugated to different lipids – shown below for convenience (Figure 10, page 35), wherein in R (corresponding to instant L) represents the lipophilic head group, and X is either –(CH2)2- or -CH2-O-CH2-.
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Regarding claim 2, Mura discloses cholesterol and oleic acid derivatives (Figure 10).
While Mura doesn’t specifically disclose a prodrug wherein the drug (D) (PTX in the example above) is attached to an acetal-containing linker (BL) through a carbonate (-O-C(O)-O-); the teachings of Jo and Zaro are relied upon for these disclosures.
Jo discloses a PTX prodrug of Formula 1 below, which is obtained by introducing their self-immolating linker which is spontaneously decomposed (hydrolyzed) to deliver PTX and a water-soluble PEG-polymer (col. 4, lines 59-65); wherein D is PTX; R’ can be H or -CH3; X can be -O- (reading on instant BL – acetal); m is an integer 1-6; and n is an integer 10-1000; R can be -OCH3 (col. 3, lines 5-26). Jo discloses their prodrug shows good bioavailability and reduced side effects (col. 1, para. 1).
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Zaro teaches that the combination of lipid drug delivery systems with prodrugs offers several advantages, such as: (i) increased half-life, allowing for less frequent dosing; (ii) increased absorption through the intestines for oral drug absorption and to the CNS for brain delivery; (iii) lipid delivery systems can enhance drug targeting; (iv) can be used to target the lymphatic system, thus bypassing the liver and avoiding first-pass metabolism; (v) while hydrophilic compounds are quickly excreted, lipophilic drugs tend to be easily reabsorbed across the tubular epithelium back into circulation, thus prolonging their circulation time; (vi) Renal clearance of lipophilic drugs is further reduced by the increased binding to plasma proteins, mainly albumin (abstract and page 83 col. 1). Zaro further discloses conjugation strategies for these prodrugs (para. bridging pages 83-84 and Fig. 1a). Zaro specifically mentions lipophilic prodrugs are particularly important for anticancer agents, which are often hydrophilic molecules and thus rely on ligand transport (page 84, col. 2, para. 3).
Thus, Mura discloses a PTX lipid prodrug below (D is the drug payload and L is a lipid):
D-O-C(O)-CH2-O-CH2-C(O)-O-L,
Jo teaches a PEGylated PTX prodrug with the linker below:
D-O-C(O)-O-CH2-O-C(O)-(CH2)2-C(O)-PEG,
While the instant claims require:
D-O-C(O)-O-CH2-O-C(O)-(CH2)2-C(O)-L.
(which is the result of simply replacing Jo’s PEG with Mura’s lipid head).
Therefore, regarding instant claims 1 and 40-41, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute Jo’s linker into Mura’s lipid prodrug of PTX, in view of Zaro, to arrive at the instant invention. One of ordinary skill would have been motivated to do so in view of Mura’s disclosure of a PTX lipid prodrug and their teachings that lipids represent materials of choice as prodrug covalent conjugates due to their biocompatibility and low toxicity; Jo’s disclosure of a PEGylated PTX prodrug with the bivalent linker described above, which decomposes spontaneously to deliver the drug payload and offers good bioavailability and reduced side effects; and Zaro’s teachings that lipid drug delivery systems with prodrugs offers several advantages, including increased half-life and reduced clearance, while hydrophilic compounds, such as Jo’s, are quickly excreted. One of ordinary skill would have had a reasonable expectation of success in view of Mura’s disclosure of different anticancer prodrugs comprising lipids, including a PTX with cholesterol prodrug; Jo’s disclosure of how their linker is prepared and linked to a drug to arrive at the desired prodrug (col. 3); and Zaro’s further guidance that lipophilic prodrugs are particularly important for anticancer agents.
The substitution of one known element for another yields predictable results to one of ordinary skill in the art. See MPEP 2143 (B).
Regarding claims 3-4, Mura in view of Jo and Zaro, as disclosed above, render the prodrugs
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obvious.
Regarding claims 5-6, Mura in view of Jo and Zaro render the BL-L portions of the prodrugs below obvious.
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Regarding claim 7, Mura in view of Jo and Zaro render the prodrug Chol-PTX-2 below obvious.
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Regarding claims 8 and 43, Applicant is advised that that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claims 8 and 43, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04.
In the present case, Zaro teaches Renal clearance of lipophilic drugs is further reduced by the increased binding to plasma proteins, mainly albumin (page 83, col. 1, lines 15-17). Furthermore, per MPEP 2112 (I): "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel."
Regarding claim 21, Jo discloses a pharmaceutical composition comprising their prodrugs, further comprising acceptable additives (reading on carriers) (col. 7, lines 51-58 and Jo’s claim 11).
Regarding claim 42, Mura teaches SN-38 as a topoisomerase inhibitor used in cancer therapy, which has been disclosed as a lipid prodrug in the art (Figure 1, page 27), thus suggesting the instant invention in view of Jo and Zaro. Applicant is reminded that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
Claims 9-20, 32, and 44-54 are rejected under 35 U.S.C. 103 as being unpatentable over Mura et al. (Journal of Controlled Release, 208, 2015, 25–41 – previously cited) (“Mura”); in view of Jo et al. (US 6,703,417 B2 – previously cited) (“Jo”); further in view of Zaro et al. (The AAPS Journal, 17, 2015, 83-92 – previously cited) (“Zaro”).; as applied to claims 1-8, 21, and 40-43; further in view of Lin et al. (WO 2017/201528 A1 – cited in the IDS – previously cited) (“Lin”).
The teachings of Mura, Jo, and Zaro are disclosed above and incorporated herein.
While Mora in view of Jo and Zaro does not specifically teach: (i) a nanoparticle comprising a core comprising a metal-organic matrix material and a coating layer comprising a lipid layer or a lipid bilayer, wherein the coating layer comprises one or more prodrug (claim 9); (ii) wherein the metal-organic matrix comprises a nanoscale coordination polymer comprising a metal bisphosphonate comprising a multivalent metal ion and a bisphosphonate, wherein the bisphosphonate is an anti-cancer agent (claims 10-11 and 44-48); (iii) wherein the core comprises an embedded anti-cancer agent (claim 12); (iii) wherein the core comprises at least two anticancer agents (claim 13 and 49-50); (iv) wherein the coating layer comprises a lipid bilayer comprising a cationic lipid and/or a functionalized lipid (functionalized with a nucleic acid that is covalently bonded or electrostatically bound) and wherein the nucleic acid is siRNA, miRNA, and AS ODN (claims 16-17 and 53); (v) wherein the nanoparticle further comprises one or more passivating agents (claim 18 and 54); (vi) wherein the nanoparticle is about 20-140 nm (claim 19); (vii) wherein the nanoparticle further comprises a plasma protein; or (viii) a pharmaceutical formulation comprising the nanoparticle and a carrier (claim 32); the teachings of Lin are relied upon for these disclosures.
Lin speaks to a nanoparticle for delivery of therapeutic agents (Lin’s claims 1 and 25), the nanoscale comprising a core comprising a metal-organic matrix and a prodrug similar to the instant prodrugs, except that their group corresponding to -BL- comprises a disulfide bond instead of an -acetal- group (see example of their group corresponding to instant -BL-L below – taken from Lin’s claim 3). Lin further discloses the nanoparticle further comprising one or more coating agents or layers covering at least a portion of the outer surface of the metal-organic matrix material core (page 10, lines 4-5).
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Therefore, regarding the nanoparticle formulation of instant claim 9, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to prepare a nanoparticle comprising Mura’s prodrug, in view of Jo and Zaro, further in view of Lin’s disclosure. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of the lipid prodrug obtained from the combination of the teachings from Mura, in view of Jo and Zaro (see previous section); Mura’s teachings that lipids have been widely used as building blocks for the design of various prodrugs due to their ability to self-assemble and to be incorporated into lipid/polymer matrices, allowing drugs to be delivered through a nanoparticulate form (abstract); and Lin’s disclosure of nanoparticle formulations for the delivery of therapeutic agents comprising a metal-organic matrix and a lipid prodrug.
Regarding claims 10 and 44, Lin discloses the nanoparticle wherein the metal organic material comprises a metal bisphosphonate coordination polymer, comprising a multivalent metal ion and a bisphosphonate (page 10, lines 23-27; and claims 40-41), wherein the metal ion is selected from the group consisting of Ca2+, Mg2+, Mn2+, Zn2+, and combinations thereof.
Regarding claims 11 and 45-46, Lin discloses the nanoparticle wherein the bisphosphonate is a chemotherapeutic prodrug, optionally a cisplatin or oxaliplatin prodrug (reading on anticancer agent) (page 10, last para), specifically mentioning [Pt(NH3)2Cl2(OH)2] etc.
Regarding claim 12, Lin discloses their nanoparticle can further comprise at least one non-nucleic acid chemotherapeutic agent embedded in pores or hollow cavities within the core (page 62, lines 13-18).
Regarding claims 14 and 51, Mura teaches SN-38 as a topoisomerase inhibitor used in cancer therapy, which has been disclosed as a lipid prodrug in the art (Figure 1, page 27). Lin discloses their nanoparticle may comprise a metal bisphosphonate coordination polymer comprising a multivalent metal ion and a bisphosphonate, wherein the bisphosphonate may be an oxaliplatin prodrug (page 10, lines 18-30).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to prepare a nanoparticle comprising a metal bisphosphonate core comprising a multivalent metal ion and a bisphosphonate, wherein the bisphosphonate is oxaliplatin, and wherein the prodrug corresponds to Chol-SN-38. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Mura’s disclosure of SN-38 and lipid prodrugs thereof; Jo’s teachings of a carbonate-acetal linker for a related anti-cancer agent that leads to good bioavailability and reduced side effects; Zaro’s teachings that lipid drug delivery systems with prodrugs offers several advantages, including increased half-life and reduced clearance, while hydrophilic compounds, on the other hand, are quickly excreted; and Lin’s disclosure of all the components of the instantly claimed nanoparticle. A person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 [R-6] KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
Further regarding claim 51, Lin discloses the nanoparticle wherein the metal organic material comprises a metal bisphosphonate coordination polymer, comprising a multivalent metal ion, like Zn2+ (page 10, last para, last line).
Regarding claims 13, 15 and 47-50, Mura discloses gemcitabine monophosphate (GMP) as another anti-cancer drug which has been used as an anticancer lipid-prodrug (reading on embedded hydrophilic anti-cancer agent) (Table 1, page 28, Entry 3 in Drugs col.) and Lin discloses their nanoparticle may contain more than one chemotherapeutic agent (page 9, lines 29-31). Lin discloses their nanoparticle can further comprise at least two chemotherapeutic agents incorporated in the metal organic matrix core (page 9, lines 29-31); and that their nanoparticle formulation may comprise other embedded components (page 62, para. 1).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention to include an embedded additional anti-cancer agent, such as GMP, into Mura in view of Jo and Zaro’s composition. One of ordinary skill would have been motivated to do so, with a reasonable expectation of success in view of the teachings from Mura, Jo, Zaro, and Lin. Furthermore, Applicant is advised with respect to a mixture of the two claimed reagents, the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” See MPEP2144.06. It is therefore obvious to provide a mixture of the two agents.
Regarding claims 16 and 52, Lin discloses their nanoparticle wherein the coating layer comprises a cationic lipid and/ or a functionalized lipid with a group that can bond to a nucleic acid, and wherein at least one nucleic acid is covalently bonded to the functionalized lipid and/or attached to the cationic lipid via electrostatic interactions (page 10, lines 10-13). Further regarding claim 52, Lin specifically discloses the lipid bilayer comprises a mixture comprising one or more of a thiol- or dithiol- functionalized 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE), 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), and 1,2-dioleoyl-sn- glycero-3-phosphocholine (DOPC) (page 10, para. 2).
Regarding claims 17 and 53, Lin discloses their nanoparticle may further comprise at least one nucleic acid therapeutic agent, which can be siRNA, miRNA, or AS ODN (page 60, lines 20-25).
Regarding claims 18 and 54, Lin discloses their nanoparticle may further comprise at least one passivating agent, such as a RGD peptide (page 64, lines 19-21).
Regarding claim 19, Lin discloses their nanoparticle has an average diameter between 20-140 nm (page 10, lines 1-2).
Applicant is advised, that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 20, Applicant is reminded that that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claim 20, must give “meaning and purpose to the manipulative steps.”
Claim 20, as worded, refers to the nanoparticle, as disclosed by Mura in view of Jo, Zaro, and Lin, wherein the nanoparticle adsorbs plasma proteins in the plasma of the subject, resulting in active transport to LDL. Applicant is advised that Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art suggests the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Furthermore, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id. See MPEP 2112 (I).
Furthermore, in the present case, Mura teaches that modification of liposomes with Apolipoprotein-E (Apo-E) (9 molecules/liposome) was exploited as a strategy to deliver the prodrug to malignant cells, by targeting the low-density lipoprotein (LDL) receptors overexpressed in several tumors (page 34, col. 2, para. 3). In addition, Zaro teaches their lipid-prodrugs are designed to target specific sites either via selective absorption of active drug at the target site (page 83, col. 2, 2 last para.).
Regarding claim 32, Lin discloses a pharmaceutical composition comprising their nanoparticle and an acceptable carrier (Lin’s claim 56).
Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Mura et al. (Journal of Controlled Release, 208, 2015, 25–41 – previously cited) (“Mura”); in view of Jo et al. (US 6,703,417 B2 – previously cited) (“Jo”); further in view of Zaro et al. (The AAPS Journal, 17, 2015, 83-92 – previously cited) (“Zaro”).; and Lin et al. (WO 2017/201528 A1 – cited in the IDS – previously cited) (“Lin”); as applied to claims 9-20, 32, and 44-54; further in view of Almer et al. (Current Medicinal Chemistry, 2015, 22, 3631-3651) (“Almer”).
The teachings of Mura, Jo, Zaro, and Lin are disclosed above and incorporated herein.
Mura teaches that modification of liposomes with Apolipoprotein-E (Apo-E) (9 molecules/liposome) was exploited as a strategy to deliver the prodrug to malignant cells, by targeting the low-density lipoprotein (LDL) receptors overexpressed in several tumors (page 34, col. 2, para. 3).
Zaro teaches their lipid-prodrugs are designed to target specific sites either via selective absorption of active drug at the target site (page 83, col. 2, 2 last para.).
While Mura in view of Jo, Zaro, and Lin do not teach Apolipoprotein-B100 (apo-B100); the teachings of Almer are relied upon for these disclosures.
Almer teaches the integration of lipoprotein-related or apolipoprotein-targeted nanoparticles as pharmaceutical carriers opens new therapeutic and diagnostic avenues in nanomedicine, including cancer therapies (abstract). Almer teaches LDL receptor, also named the B/E-receptor, apart from apo-B100 also recognizes apolipoprotein E (apo-E) containing lipoproteins (page 3633, col. 1, lines 20-30).
Therefore, it would have been prima facie obvious to one of ordinary skill to expect the nanoparticles of Mura in view of Jo, Zaro, and Lin to absorb to apo-B100 plasma proteins, resulting in active transport to tumors via LDLR, as taught by Almer. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Mura in view of Jo, Zaro, and Lin disclose their nanoparticle lipid compositions; Mura’s teaching that modification of liposomes Apo-E was exploited as a strategy to deliver the prodrug to malignant cells; and Almer’s teaching that LDL receptor recognizes apo-B100 and apo-E containing lipoproteins.
Applicant is reminded that Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art suggests the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Furthermore, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. The court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.”
Response to Arguments
Drawings
The replacement sheet for Figures 1 and 2 is acknowledged and has been entered. The objection to the Drawings has been withdrawn.
Claims/ Objection to Claims
New claims are acknowledged and have been entered. No new matter has been introduced.
Applicant’s arguments, see page 20, filed 02/09/2026, with respect to objections to the claims have been fully considered and are persuasive. The objection of the claims has been withdrawn.
Claim Rejections - 35 USC § 112(b)
Applicant’s arguments, see page 20-21, filed 02/09/2026, with respect to 35 USC § 112(b) rejections of the claims have been fully considered and are persuasive. The 35 USC § 112(b) rejections of the claims have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 02/09/2026 have been fully considered but they are not persuasive.
Applicant argues that the office has applied hindsight reasoning in advancing the instant rejection, and cites MPEP 2141 to say that “the mere fact that references can be combined does not render the resulting combination obvious unless the results would have been predictable to one of ordinary skill in the art” – however, applicant fails to specifically state how the teachings of the art cited in the rejections presented fail to render the instant claims obvious. Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)).
Applicant argues that Mura and Zaro are review articles that broadly propose a range of possible approaches for lipid carriers for prodrugs and that, when considered as a whole, Jo discloses approaches for the preparation of water-soluble prodrugs; stating that one of ordinary skill would not have been motivated to combine Jo with Mura, Zaro, and Lin. Applicant states the present invention includes methods and compositions to co-deliver combination chemotherapies via active targeting of LDLR in tumors. Applicant then cites MPEP 2143.03 to state that the instant claims are not obvious and allowable.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to Applicant’s arguments that the claims are allowable; Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
In response to Applicant’s arguments that Mura and Zaro are reviews and too broad, or that Jo discloses approaches for the preparation of water-soluble prodrugs; Applicant is advised that 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). Furthermore, Per MPEP 2123 (I): “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.").”
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See 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), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Mura discloses lipid prodrug nanocarriers in cancer therapy. Mura discloses a series of paclitaxel (PTX) prodrugs conjugated to different lipids – shown in the 103-section above (Figure 10, page 35), wherein in R (corresponding to instant L) represents the lipophilic head group, and X is either –(CH2)2- or -CH2-O-CH2-.
Jo discloses a PTX prodrug of Formula 1, which is obtained by introducing their self-immolating linker which is spontaneously decomposed (hydrolyzed) to deliver PTX and a PEG-polymer (col. 4, lines 59-65); wherein D is PTX; R’ can be H or -CH3; X can be -O- (reading on instant BL – acetal); m is an integer 1-6; and n is an integer 10-1000; R can be -OCH3 (col. 3, lines 5-26).
Zaro teaches that the combination of lipid drug delivery systems with prodrugs offers several advantages, such as: (i) increased half-life, allowing for less frequent dosing; (ii) increased absorption through the intestines for oral drug absorption and to the CNS for brain delivery; (iii) lipid delivery systems can enhance drug targeting; (iv) can be used to target the lymphatic system, thus bypassing the liver and avoiding first-pass metabolism; (v) while hydrophilic compounds are quickly excreted, lipophilic drugs tend to be easily reabsorbed across the tubular epithelium back into circulation, thus prolonging their circulation time; (vi) Renal clearance of lipophilic drugs is further reduced by the increased binding to plasma proteins, mainly albumin (abstract and page 83 col. 1). Zaro further discloses conjugation strategies for these prodrugs (para. bridging pages 83-84 and Fig. 1a). Zaro specifically mentions lipophilic prodrugs are particularly important for anticancer agents, which are often hydrophilic molecules and thus rely on ligand transport (page 84, col. 2, para. 3).
Thus, Mura discloses a PTX lipid prodrug below (D is the drug payload and L is a lipid):
D-O-C(O)-CH2-O-CH2-C(O)-O-L,
Jo teaches a PEGylated PTX prodrug with the linker below:
D-O-C(O)-O-CH2-O-C(O)-(CH2)2-C(O)-PEG,
While the instant claims require:
D-O-C(O)-O-CH2-O-C(O)-(CH2)2-C(O)-L.
(which is the result of simply replacing Jo’s PEG with Mura’s lipid head).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute Jo’s linker into Mura’s lipid prodrug of PTX, in view of Zaro, to arrive at the instant invention. One of ordinary skill would have been motivated to do so in view of Mura’s disclosure of a PTX lipid prodrug and their teachings that lipids represent materials of choice as prodrug covalent conjugates due to their biocompatibility and low toxicity; Jo’s disclosure of a PEGylated PTX prodrug with the bivalent linker described above, which decomposes spontaneously to deliver the drug payload and offers good bioavailability and reduced side effects; and Zaro’s teachings that lipid drug delivery systems with prodrugs offers several advantages, including increased half-life and reduced clearance, while hydrophilic compounds, such as Jo’s, are quickly excreted. One of ordinary skill would have had a reasonable expectation of success in view of Mura’s disclosure of different anticancer prodrugs comprising lipids, including a PTX with cholesterol prodrug; Jo’s disclosure of how their linker is prepared and linked to a drug to arrive at the desired prodrug (col. 3); and Zaro’s further guidance that lipophilic prodrugs are particularly important for anticancer agents. Applicant is reminded that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
In response to Applicant’s argument that the present invention includes methods and compositions to co-deliver combination chemotherapies via active targeting of LDLR in tumors, Applicant is advised that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02.
Conclusion
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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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627