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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/10/25 has been entered.
Claims 1, 5, 12, 15, 47-49, 52, 57, 62, 68, 70, 73, 76, 79, and 81-83 are pending.
Claims 1, and 52 have been amended by Applicant.
Claims 1, 5, 12, 15, 47-49, 52, 57, 62, 68, 70, 73, 76, 79, and 81-83 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Maintained
Claim Rejections - 35 USC § 103
Claims 49 and 82 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Liu et al (US 2015/0118216 A1; 4/30/15) in view of Tseng et al (WO 2009/142893 A2; 11/26/09).
Liu et al teaches delivering proteins, including anionic (negatively charged) proteins, into cells using compositions comprising cationic (positively charged) lipids (same as “cationic transfection agent” carriers), wherein the negatively charged proteins complex with the positively charged lipids and are efficiently delivered into cells ([0004]-[0005], in particular). Liu et al further teaches such delivery can be performed with naturally negatively-charged proteins or with protein fusions/conjugates in which a protein to be delivered is associated with a negatively (or “supernegatively” supercharged) charged protein ([0005], in particular). Liu et al further teaches such delivery wherein the protein to be delivered is a “functional effector protein”, such as an antibody that is fused with a supernegatively charged protein to allow for delivery of the protein into the interior of cells ([0006], in particular). Liu et al further teaches such protein fusions/conjugates comprising the supercharged protein (such as supernegatively charged anionic polypeptide) and the protein to be delivered (such as an antibody) are made by covalently or non-covalently linking, ligating, or fusing the supercharged protein and the protein to be delivered and mixing with cationic (positively charged) lipids (“transfection agent”) ([0005], [0012], and [0014], in particular).
Liu et al teaches making a composition for cytoplasmic delivery by covalently or non-covalently linking, ligating, or fusing the supernegatively (anionic) charged polypeptide 3xFLAG sequence to Cre polypeptide and mixing the conjugate with with cationic RNAiMAX lipids ([0124] and Fig. 33C, in particular). The 23-amino acid 3xFLAG sequence “consists of” MDYKDHDGDYKDHDIDYKDDDDK (SEQ ID NO:48; negatively charged aspartic acid is shown bold and underlined). It is further noted Liu et al further identifies (-30)GFP as a supernegatively/anionic charged proteins that comprise SEQ ID NO: 21 or SEQ ID NO:40 ([0088] and [0166], in particular). At [0119], Liu et al further teaches supernegatively charged polypeptides of composition for cytoplasmic delivery of a protein that are non-covalently linked, ligated, or fused the protein comprise “a sequence of at least 10, at least 20, at least 30, at least 40, at least 50, at least 75, or at least 100 consecutive amino acids.” Liu et al further teaches said delivery wherein the functional effector protein fused or conjugated with the supernegatively charged protein is administered to a subject to therapeutically treat a disease of the subject ([0019] and [0152], in particular).
While Liu et al teaches a Liu et al a supernegatively/anionic charged polypeptide that is 23 amino acids in length and has 11 negatively charged amino acids (SEQ ID NO:48), Liu et al does not specifically teach a supernegatively/anionic charged polypeptide that is “40 amino acid residues or fewer in length and having at least 15 negatively charged amino acids.” However, these deficiencies are rendered obvious by Liu et al alone and/or are made up in the teachings of Tseng et al.
Tseng et al teaches supernegatively/anionic charged polypeptide used for delivery that comprise 30-100% negatively charged glutamic acid and/or aspartic acid residues (pages 42-43, in particular). Tseng et al further teaches such supernegatively/anionic charged polypeptide include polypeptides that having lengths of about 20, 30, or 40 amino acids (lines 1-5 on page 43, in particular). Tseng et al further teaches such supernegatively/anionic charged polypeptide include polypeptides having various percentages, including 40-100%, of negatively charged glutamic acid and/or aspartic acid residues (last full paragraph on page 42, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer the compositions of Liu et al wherein the supernegatively/anionic charged polypeptide is a supernegatively/anionic charged polypeptide having just any length of 20-100 amino acids, as taught by Liu et al, and having 40-100% negatively charged glutamic acid and/or aspartic acid residues, as taught by Tseng et al, because (i) the supernegatively/anionic charged polypeptide of Liu et al is taught to be “a sequence of at least 10, at least 20, at least 30, at least 40, at least 50, at least 75, or at least 100 consecutive amino acids” and used by Liu et al for delivery and (ii) supernegatively/anionic charged polypeptides of Tseng et al include supernegatively/anionic charged polypeptides having lengths of 20-100 amino acids and having 40-100% negatively charged glutamic acid and/or aspartic acid residues used for delivery. Using such a supernegatively/anionic charged polypeptide of Tseng et al in place of a supernegatively/anionic charged polypeptide of Liu et al is an example of a simple substitution of one known element for another to obtain predictable results. Further, the amounts of negatively charged amino acids of the supernegatively/anionic charged polypeptides of Tseng et al predictably render the supernegatively/anionic charged polypeptides of the combined method as supernegative, as envisioned by Liu et al.
Further, Liu et al alone renders the claims obvious because claimed number of negative amino acids and those of the supernegatively/anionic charged polypeptide SEQ ID NO:48 used in compositions of Liu et al are close. Compositions of Liu et al include a supernegatively/anionic charged polypeptide that is 23 amino acids in length and has 11 negatively charged amino acids (SEQ ID NO:48), while instant claim 1 recites a supernegatively/anionic charged polypeptide that is “40 amino acid residues or fewer in length and having at least 15 negatively charged amino acids.” The 23 amino acids of supernegatively/anionic charged polypeptide (SEQ ID NO:48) of Liu et al are ˃47% negatively charged amino acids, while the claims broadly encompass supernegatively/anionic charged polypeptides that are 37.5-100% negative charge amino acids. MPEP 2144.05 states a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.) In the instant case, absent any showing of unexpected results or criticality, it appears the addition of four more negatively charged amino acids to SEQ ID NO:48 of Liu et al would predictably have the same ability to function as intended by Liu et al.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 9/30/25, Applicant argues Liu and Tseng do not use supernegatively/anionic charged polypeptides in the same way – Liu uses the supernegatively/anionic charged polypeptides covalently linked to cargo (as recited by the instant claims), while Tseng uses the supernegatively/anionic charged polypeptides to form a network with cationic lipids that trap or enmash cargo without attaching or fusing the supernegatively/anionic charged polypeptides to the cargo. Applicant further argues a lack of sufficient motivation to combine Liu and Tseng and substitute Tseng’s supernegatively/anionic charged polypeptides used ty Tseng to trap cargo for Liu’s supernegatively/anionic charged polypeptides fused to cargo. Applicant further cites MPEP 2144.05(III)(c) and argues neither the overall length nor total content of negatively charged amino acid residues in supernegatively/anionic charged polypeptides were recognized as “result effective” parameters to successfully deliver proteins to cytoplasm. Applicant further argues ranges of Tseng et al (2 to 100,000 amino acids containing anywhere from 30-100% of negatively charged glutamic and/or aspartic acids) are so broad that characteristics of different members would vary so enormously as to discourage optimization by a skilled artisan. Applicant further argues there is no reasonable expectation of success on the part of skilled artisan when attempting to use the system of Liu for cytoplasmic delivery of a 150 kD antibody with Tseng’s supernegatively/anionic charged polypeptides that are neither fused to the protein of interest (cargo) nor capable of delivering payloads exceeding 50 kD (see first paragraph on page 35 of Tseng).
The amendments to the claims and the arguments found in the Reply of 9/30/25 have been carefully considered, but are not deemed persuasive. The examiner agrees with the argument Liu and Tseng do not use supernegatively/anionic charged polypeptides in the same way – Liu uses the supernegatively/anionic charged polypeptides covalently linked to cargo (as recited by the instant claims), while Tseng uses the supernegatively/anionic charged polypeptides to form a network with cationic lipids that trap or enmash cargo without attaching or fusing the supernegatively/anionic charged polypeptides to the cargo.
In regards to the argument of a lack of sufficient motivation to combine Liu and Tseng and substitute Tseng’s supernegatively/anionic charged polypeptides used ty Tseng to trap cargo for Liu’s supernegatively/anionic charged polypeptides fused to cargo and no reasonable expectation of success on the part of skilled artisan when attempting to use the system of Liu for cytoplasmic delivery of a 150 kD antibody with Tseng’s supernegatively/anionic charged polypeptides that are neither fused to the protein of interest (cargo) nor capable of delivering payloads exceeding 50 kD (see first paragraph on page 35 of Tseng), the examiner disagrees. As stated above, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer the compositions of Liu et al wherein the supernegatively/anionic charged polypeptide is a supernegatively/anionic charged polypeptide having just any length of 20-100 amino acids, as taught by Liu et al, and having 40-100% negatively charged glutamic acid and/or aspartic acid residues, as taught by Tseng et al, because (i) the supernegatively/anionic charged polypeptide of Liu et al is taught to be “a sequence of at least 10, at least 20, at least 30, at least 40, at least 50, at least 75, or at least 100 consecutive amino acids” and used by Liu et al for delivery and (ii) supernegatively/anionic charged polypeptides of Tseng et al include supernegatively/anionic charged polypeptides having lengths of 20-100 amino acids and having 40-100% negatively charged glutamic acid and/or aspartic acid residues used for delivery. Using such a supernegatively/anionic charged polypeptide of Tseng et al in place of a supernegatively/anionic charged polypeptide of Liu et al is an example of a simple substitution of one known element for another to obtain predictable results. Further, the amounts of negatively charged amino acids of the supernegatively/anionic charged polypeptides of Tseng et al predictably render the supernegatively/anionic charged polypeptides of the combined method as supernegative, as envisioned by Liu et al.
In regards to the citation of MPEP 2144.05(III)(c) and argument neither the overall length nor total content of negatively charged amino acid residues in supernegatively/anionic charged polypeptides were recognized as “result effective” parameters to successfully deliver proteins to cytoplasm, the rejection is no longer based on “optimization.”
Claim Rejections - 35 USC § 103
Claim(s) 1, 12, 47-49, 52, 57, and 81-83 remain rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (US 2015/0118216 A1; 4/30/15) in view of Tseng et al (WO 2009/142893 A2; 11/26/09) as applied to claims 49 and 82 above, and further in view of Choe et al (Materials, 2016, 9(994): 1-17).
Teachings of Liu et al and Tseng et al are discussed above.
Liu et al and Tseng et al do not specifically teach conjugates of Liu et al comprising the polyanionic carrier polypeptide of Tseng et al and the protein to be delivered (such as an antibody) are made by connecting the polyanionic carrier polypeptide of Tseng et al and the protein to be delivered by linking, ligating, or fusing an antibody binding domain (AbBD) to the polyanionic carrier polypeptide of Tseng et al and linking, ligating, or fusing said AbBD to the protein to be delivered (such as antibody). However, these deficiencies are made up in the teachings of Choe et al.
Choe et al demonstrates an Fc-binding protein (including FcBP, a type of AbBD) is capable of linking antibodies to polypeptides (including GFP) for intracellular delivery (Figure 8, in particular). Choe et al further teaches a benefit of using Fc- binding proteins is that the Fc-binding proteins do not interfere with antigen binding of antibodies (page 13, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer the compositions of the combination of Liu et al and Tseng et al wherein a polyanionic carrier polypeptide of Tseng et al and an antibody to be delivered are connected by linking an Fc-binding protein of Choe et al to the polyanionic carrier polypeptide of Tseng et al and linking said Fc-binding protein of Choe et al to the antibody to be delivered because Liu et al teaches compositions wherein the compositions of a supercharged protein and the protein (including antibody) to be delivered are made by covalently or non-covalently linking the supercharged protein and the protein (including antibody) to be delivered, Choe et al teaches Fc-binding proteins do not interfere with antigen binding of antibodies, and Choe et al demonstrates an Fc- binding protein (including FcBP, a type of AbBD) is capable of covalently or non-covalently linking an antibody to a polypeptide (exemplified with GFP) for intracellular delivery by connecting a polypeptide and an antibody to be delivered by linking an Fc-binding protein of Choe et al to the protein and linking said Fc- binding protein of to the antibody to be delivered (Figure 8, in particular). This is an example of combining prior art elements according to known methods to yield predictable results. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 9/30/25, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claim(s) 1, 5, 12, 47-49, 52, 57, 62, 68, 70, 73, 76, 79, and 81-83 remains rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (US 2015/0118216 A1; 4/30/15) in view of Tseng et al (WO 2009/142893 A2; 11/26/09) and Choe et al (Materials, 2016, 9(994): 1-17), as applied to claims 1, 12, 47-49, 52, 57, and 81-83 above, and further in view of Renes et al (British Journal of Pharmacology, 1999, 126: 681-688) and Loe et al (JBC, 1996, 271(16): 9675-9682).
Teachings of Liu et al, Tseng et al, and Choe et al are discussed above.
Liu et al, Tseng et al, and Choe et al do not specifically teach administering an IgG or a method of sensitizing a tumor cell to a chemotherapeutic agent comprising administering a conjugate. However, these deficiencies are made up in the teachings of Renes et al and Loe et al.
Renes et al teaches MRP1 is a protein found in multidrug resistant tumor cells and is able to confer resistance to various drugs (including vincristine and daunorubicin) by transporting the drugs (pages 681 and 684, in particular). Renes et al further teaches the anti-MRP1 monoclonal antibody QCRL3 (same as “QCRL-3”) inhibits transport of daunorubicin and vincristine by MRP1 in assays performed with isolated membrane vesicles from multidrug resistant cell lines (Abstract, page left column of 685, and Figure 5, in particular, in particular).
The abstract of Loe et al teaches the QCRL-3 antibody of Renes et al is directed against an intracellular epitope of MRP (same as “MRP1”). Loe et al further teaches QCRL-3 antibody of Renes et al is an IgG (left column on page 9676, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a subject with tumor cells exhibiting MRP1-mediated multidrug resistance (MDR) to daunorubicin and vincristine comprising generating and administering to said subjects (i) compositions of the combination of Liu et al, Tseng et al, and Choe et al using cationic (positively charged) lipids of Liu et al in which the antibody of the compositions is associated with a polyanionic carrier polypeptide of Tseng et al to be delivered into cells is QCRL-3 antibody of Renes et al followed by (ii) daunorubicin and vincristine administration because Renes et al teaches MRP1 is a protein found in multidrug resistant tumor cells and is able to confer resistance to various drugs, Renes et al teaches the anti-MRP1 antibody QCRL-3 inhibits transport of daunorubicin and vincristine by MRP1 in an MRP1 model using membrane vesicles from multidrug resistant cell lines, Loe et al teaches the QCRL-3 antibody of Renes et al is directed against an intracellular epitope of MRP1, and the compositions using cationic (positively charged) lipids of Liu et al provides a mechanism for intracellular delivery of QCRL-3 in order for QCRL-3 to interact with its binding epitope on MRP1 and sensitize the tumor cells to vincristine and daunorubicin by inhibiting MRP1-mediated transport of vincristine and daunorubicin. This is an example of combining prior art elements according to known methods to yield predictable results.
Regarding claim 79, the Fc-receptor binding protein of Choe et al of the combined method is an AbBD that binds just any Fc domain – including an Fc domain of an anti-RelA IgG antibody. Claim 79 does not require the administered composition to comprise an anti-RelA antibody. Further, while the cited references do not demonstrate the combined method results in inhibiting NF-kB transcription and/or reducing RelA nuclear translocation in a cancer cell, such inhibition and reduction would predictably occur by the combined method because cancer cells killed by the combined method would not predictably transcribe NF-KB and/or exhibit nuclear translocation of RelA. One of skill in the art would recognize vincristine of the combined method kills cancer cells by inducing cell cycle arrest and triggering apoptosis.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 9/30/25, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claim(s) 1, 12, 15, 47-49, 52, 57, and 81-83 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (US 2015/0118216 A1; 4/30/15) in view of Tseng et al (WO 2009/142893 A2; 11/26/09) and Choe et al (Materials, 2016, 9(994): 1-17), as applied to claims 1, 12, 47-49, 52, 57, and 81-83 above, and further in view of Cortesi et al (New Biotechnology, 2014, 31(1): 44-54).
Teachings of Liu et al, Tseng et al, and Choe et al are discussed above.
Liu et al, Tseng et al, and Choe et al do not specifically teach compositions for delivering proteins, including anionic (negatively charged) proteins, into cells using compositions comprising cationic (positively charged) lipid carriers wherein the cationic lipids are described as cationic lipid “nano-carriers”. However, these deficiencies are made up in the teachings of Cortesi et al.
Cortesi et al teaches cationic lipid nano-carriers as cationic lipids used to deliver DNA into cells (Abstract, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer the compositions of Liu et al, Tseng et al, and Choe et al comprising cationic (positively charged) lipid carriers for delivering proteins, including anionic (negatively charged) proteins, into cells wherein the cationic lipids are just any cationic lipids, including “nano-carrier” cationic lipids of Cortesi et al because one of skill in the art would recognize anionic proteins and cationic lipid nano-carriers would form complexes due to opposing charges and Liu et al teaches anionic protein : cationic lipid complexes are efficiently delivered into cells ([0005], in particular). Substituting the cationic lipid nano-carriers in place of the cationic lipid carriers of the compositions of Liu et al, Tseng et al, and Choe et al is an example of a simple substitution of one known element for another to obtain predictable results. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 9/30/25, Applicant repeats arguments addressed above.
Conclusion
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/SEAN E AEDER/Primary Examiner, Art Unit 1642