Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Status of Application/Amendment/Claims
Applicant's response filed 10/20/2025 has been considered. Rejections and/or objections not reiterated from the previous office action mailed 04/21/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
With entry of the amendment filed on 10/20/2025, claims 1-34 are pending in the application.
The 103 rejection is maintained and slightly modified due to new claims 31-34.
The Double Patenting rejections are maintained and slightly modified due to new claims 31-34.
Information Disclosure Statement
The submission of the Information Disclosure Statement on 10/20/2025 is in compliance with 37 CFR 1.97. The information disclosure statement has been considered by the examiner and signed copies have been placed in the file.
New Claim Rejections – necessitated by claim amendments
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.
Claim 32 is 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 32 recites “the composition of claim 3, wherein the mixture of diastereomers has a diastereomeric excess less than about 55%”. The instant specification at [0307] describes the lipid as having is “enriched in one diastereomer, such that the lipid comprises at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% diastereomeric excess.” (emphasis added). The specification does not describe or contemplate the mixture of diastereomers as having a diastereomeric excess less than about 55%. Therefore this limitation is considered new matter.
If Applicant believes that such support is present in the specification and claimed priority documents, Applicant should point, with particularity, to where such support is to be found.
The word “about” is not defined in the specification and the limitation “less than about 55%” is interpreted as range such that about 55% can encompass percentages 55%, slightly greater than or slightly less than 55% .
Claim Rejections - 35 USC § 103 – modified slightly due to new claims
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the
invention was made.
Claims 1-34 are rejected under pre-AIA 35 U.S.C. 103(a) as being obvious over Yaworski et al. (US Patent No. 8,058,069 of record cited on IDS filed 10/31/2024) in view of Gaucheron et al. ("Synthesis and properties of novel tetraalkyl cationic lipids." Bioconjugate chemistry 13.3 (2002): 671-675) and Lee et al. (WO 2011/000108 which has priority to Provisional 61,351,275 filed 06/03/2010).
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 pre-AIA 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.
Regarding claims 1 and 11-15, Yaworski et al. teach, in claim 1, a nucleic acid-lipid particle comprising:
(a) a nucleic acid;
(b) a cationic lipid comprising from 50 mol % to 65 mol % of the total lipid present in the particle;
(c) a non-cationic lipid comprising a mixture of a phospholipid and cholesterol or a derivative thereof, wherein the phospholipid comprises from 4 mol % to 10 mol % of the total lipid present in the particle and the cholesterol or derivative thereof comprises from 30 mol % to 40 mol % of the total lipid present in the particle; and
(d) a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol % to 2 mol % of the total lipid present in the particle.
Regarding claims 1 and 31, Yaworski et al. teach the cationic lipid can comprises a “In some cases, the cationic lipids comprise a protonatable tertiary amine (e.g., pH titratable) head group.” (col.12 ln. 65-67).The instant specification describes cationic lipids as “titratable cationic lipids” as pH-titratable amino head group (see [0308]).
Regarding claims 5-10, Yaworski et al. teach the nucleic acid is RNA or mRNA (see col. 10), teach the lipid has protonatable groups (col. 12, lines 51-68) and teach the PEG can be at least PEG-DAG (see claims 10-12).
Regarding claims 23-25, Yaworski et al. teach the mean diameter of the particles are between 40 – 150 nM (see claim 19).
Regarding claims 22, 26 and 27, Yaworski et al. further teach the lipid is fully encapsulated (see claim 17) and teach the particles have a lipid:nucleic acid ratio from about 2 to about 25 (see col.23 lines 35-45).
Regarding claims 28-30, Yaworski et al. teach a pharmaceutical composition and methods of introducing into cells and in vivo delivery (see claim 22 and col. 3 lines 65-68).
Regarding claims 33 and 34, Yaworski et al. teach nucleic acid can be fully encapsulated within the lipid particle, which meets the limitations of “at least about 80%” and “at least about 90%”.
Yaworski et al. does not explicitly teach the morphology limitation of the particles being at least about 95% electron dense.
The instant specification teach in [0479] For all SNALP formulations analyzed, whether made by the SDM or the DDM, the resulting SNALP particles were categorized using the following criteria: (a) Non- lamellar particles: dense particles with no visible lamellar structures (e.g., no bilayers); and (b) Lamellar particles: particles possessing bilayer structures, including those with multiple compartments, LUVs and MLVs. The Non-lamellar particles would be considered electron dense from this description in the instant specification. Further the instant specification describes formulations of the nucleic acid-lipid particles (SNALP) include 1:57 and 1:62 formulations (see [0471]) and describe these formulations as Non-lamellar in Figures 7 and 12.
Regarding claims 1 and 17-21, Yaworski et al. teach in col. 5 In certain embodiments, the present invention provides improved compositions for the delivery of interfering RNA such as siRNA molecules. In particular, the Examples herein illustrate that the improved lipid particle formulations of the invention are highly effective in downregulating the mRNA and/or protein levels of target genes. Furthermore, the Examples herein illustrate that the presence of certain molar ratios of lipid components results in improved or enhanced activity of these lipid particle formulations of the present invention. For instance, the "1:57 SNALP" and "1:62 SNALP" formulations described herein are exemplary formulations of the present invention that are particularly advantageous because they provide improved efficacy and tolerability in vivo, are serum-stable, are substantially non-toxic, are capable of accessing extravascular sites, and are capable of reaching target cell populations.
The claim limitation “at least about 95% of the particles in the plurality of particles are electron dense” is an inherent feature taught by Yaworski et al. because the SNALP formulations in Yaworski et al. are the same or essentially the same since they disclose the same process of making that would naturally result in the SNALP having the claimed morphological property of being at least about 95% electron dense. Thus the morphology limitation of claim 1 is inherently disclosed by the Yaworski et al. as described above. A limitation is inherent if it is the “natural result flowing from” the prior art’s explicit disclosure. Id. at 1379. A patent “can be invalid based on inherency when the patent itself makes clear that a limitation is ‘not an additional requirement imposed by the claims . . . but rather a property necessarily present’.” Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1332 (Fed. Cir. 2020) (quoting In re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009)).
While Yaworski et al. teach the “cationic lipid comprising alkyl chains” (col. 12 ln. 54), Yaworski et al. does not explicitly teach the cationic lipid comprises three or more fatty acid or fatty alkyl chains as in instant claim 1.
Regarding claims 1-4, Lee et al. teach the cationic lipid comprise three or more fatty alkyl chains [0274] and further teach a nucleic acid lipid particle is enriched in one diastereomer, such that the cationic lipid has at least about 55% diastereomeric excess (see 0267 page 82). It would therefore have been obvious to enrich the lipid with one diastereomer with at least about 55% diastereomeric excess as taught by Lee et al.
Regarding claims 1 and 16, the art of Gaucheron et al. teach that [c]onsiderable effort has therefore been devoted to synthesizing new cationic lipids that have improved transfection properties. (page 671 first para.). Gaucheron et al. teach the ability of cationic lipids to facilitate intracellular delivery is related to their ability to induce the non-bilayer hexagonal HII phase in combination with anionic lipids (11). In particular this proposal suggests that the most potent cationic lipids are those that are the most effective inducers of HII phase organization. The ability of lipids to adopt the H II phase has been related to their dynamic “molecular shape” properties. Within this framework lipids with a small cross-sectional area in the headgroup region and a larger acyl chain cross-sectional area exhibit a “cone” shape compatible with H II phase organization (12). In this regard a direct method to increase the cone-shaped character of a given lipid is to increase the number of alkyl chains associated with the headgroup (page 671 second para.).
Gaucheron et al. also teach cationic lipids that contain four alkyl chains (see Scheme 1 page 673) and demonstrates a nucleic acid-lipid conjugate comprising plasmid DNA and a cationic lipid comprising four alkyl chains had higher transfection efficiency than a cationic lipid with a single alkyl chain (see Figure 4). Thus it would have therefore been obvious for one of skill in the art to incorporate a hexagonal HII phase into the lipid of Yaworski et al. to facilitate intracellular delivery. Further given Lee et al. teach cationic lipids can comprise three or more fatty alkyl chains and Gaucheron et al. found that a cationic lipid with more alkyl chains had a higher transfection efficacy, it would have been obvious to try adding three or more fatty alkyl chains to the cationic lipid of Yaworski et al. to improve the shape of the cationic lipid to facilitate more efficient intracellular delivery.
In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.
Because the prior art teach a design need to change the shape of the cationic lipid to aid in improvement of delivery and because there was a finite number of predictable solutions, such as adding 3-4 additional alkyl chains, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Double Patenting – modified due to claim amendments
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,129,467. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a composition comprising a nucleic acid-lipid particle comprising (a) a nucleic acid, (b) a cationic lipid (c) a non-cationic lipid and (d) a conjugated lipid that inhibits aggregation of particles. Both claim sets are further drawn to the nucleic acid being a RNA or mRNA, the cationic lipid comprises a mixture of diastereomers, the non-cationic lipid is a mixture of a phospholipid and cholesterol, the conjugated lipid being PEG, the electron dense particles comprising HII or cubic phase structure, the electron-dense particles are 96-100%, the particles have a mean diameter of between 60 to 130 nm, a pharmaceutical composition comprising the composition of claim 1 and to methods of in vivo delivery.
Patent ‘467 does not claim the cationic lipid comprises three or more fatty acid or fatty alkyl chains. Lee et al. and Gaucheron et al. (cited above) teach cationic lipids that contain four alkyl chains (see Scheme 1 page 673) and demonstrates a nucleic acid-lipid conjugate comprising plasmid DNA and a cationic lipid comprising four alkyl chains had higher transfection efficiency than a cationic lipid with a single alkyl chain (see Figure 4). It would have therefore been obvious to try adding three or more fatty alkyl to the cationic lipid of Patent ‘467 to improve the shape of the cationic lipid to facilitate more efficient intracellular delivery.
Patent ‘467 does not claim the cationic lipid is a titratable cationic lipid. Heyes, James, et al. ("Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids." Journal of controlled release 107.2 (2005): 276-287 cited on 892 mailed 04/21/2025) teach the use of cationic lipids with pH titratable head groups and teach the advantage of using a titratable head group allows for the cationic charge that facilitates fusion with the anionic lipid containing the endosomal bilayer (see page 284 second para).
Patent ‘467 does not teach the diastereomeric excess is less than about 55%. Lee et al. (cited above) teach a nucleic acid lipid particle is enriched in one diastereomer, such that the cationic lipid comprises at least about 55% diastereomeric excess (see 0267 page 82). It would therefore have been obvious to enrich the lipid with one diastereomer with at least about 55% diastereomeric excess as taught by Lee et al.
Thus the claims are not patentably distinct.
Claims 1-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,364,435. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a composition comprising a nucleic acid-lipid particle comprising (a) a nucleic acid, (b) a cationic lipid (c) a non-cationic lipid and (d) a conjugated lipid that inhibits aggregation of particles. Both claim sets are further drawn to the nucleic acid being a RNA or mRNA, the cationic lipid comprising from 50-85% mol of the total lipid, the cationic lipid comprises a mixture of diastereomers, the non-cationic lipid is a mixture of a phospholipid and cholesterol, the conjugated lipid being PEG, the particles have a mean diameter of between 60 to 130 nm, a pharmaceutical composition comprising the composition of claim 1 and to methods of in vivo delivery.
Patent ‘435 does not claim the conjugated particles are at least 95% electron-dense and does not claim the cationic lipid comprises three or more fatty acid or fatty alkyl chains. The claim limitation “at least about 95% of the particles in the plurality of particles are electron dense” is an inherent feature taught by Patent ‘435 because the conjugated lipid in the SNALP formulations in Patent ‘435 are the same or essentially the same (comprising 1:57 and/or 1:62 see col.5 lines 56-67 and 6 lines 15-30) formulations since they disclose the same process of making that would naturally result in the SNALP having the claimed morphological property of being at least about 95% electron dense as in the instant claims. Thus the morphology limitation of claim 1 is inherently disclosed by Patent ‘435 as described above. A limitation is inherent if it is the “natural result flowing from” the prior art’s explicit disclosure. Id. at 1379. A patent “can be invalid based on inherency when the patent itself makes clear that a limitation is ‘not an additional requirement imposed by the claims . . . but rather a property necessarily present’.” Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1332 (Fed. Cir. 2020) (quoting In re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009)).
Patent ‘435 does not claim the cationic lipid comprises three or more fatty acid or fatty alkyl chains. Lee et al. and Gaucheron et al. (cited above) teach cationic lipids that contain four alkyl chains (see Scheme 1 page 673) and demonstrates a nucleic acid-lipid conjugate comprising plasmid DNA and a cationic lipid comprising four alkyl chains had higher transfection efficiency than a cationic lipid with a single alkyl chain (see Figure 4). It would have therefore been obvious to try adding three or more fatty alkyl to the cationic lipid of Patent ‘467 to improve the shape of the cationic lipid to facilitate more efficient intracellular delivery.
Patent ‘435 does not claim the cationic lipid is a titratable cationic lipid. Heyes, James, et al. ("Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids." Journal of controlled release 107.2 (2005): 276-287 cited on 892 mailed 04/21/2025) teach the use of cationic lipids with pH titratable head groups and teach the advantage of using a titratable head group allows for the cationic charge that facilitates fusion with the anionic lipid containing the endosomal bilayer (see page 284 second para).
Patent ‘435 does not teach the diastereomeric excess is less than about 55%. Lee et al. (cited above) teach a nucleic acid lipid particle is enriched in one diastereomer, such that the cationic lipid comprises at least about 55% diastereomeric excess (see 0267 page 82). It would therefore have been obvious to enrich the lipid with one diastereomer with at least about 55% diastereomeric excess as taught by Lee et al.
Thus the claims are not patentably distinct.
Claims 1-34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 8,822,668. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a composition comprising a nucleic acid-lipid particle comprising (a) a nucleic acid, (b) a cationic lipid (c) a non-cationic lipid and (d) a conjugated lipid that inhibits aggregation of particles. Both claim sets are further drawn to the cationic lipid comprising from 50-85% mol of the total lipid, the cationic lipid comprises a mixture of diastereomers, the non-cationic lipid is a mixture of a phospholipid and cholesterol, the conjugated lipid being PEG, the particles have a mean diameter of between 60 to 130 nm, a pharmaceutical composition comprising the composition of claim 1 and to methods of in vivo delivery.
Patent ‘668 does not claim the conjugated particles are at least 95% electron-dense, does not claim the nucleic acid is a siRNA and does not claim the cationic lipid comprises three or more fatty acid or fatty alkyl chains. The claim limitation “at least about 95% of the particles in the plurality of particles are electron dense” is an inherent feature taught by Patent ‘668 because the conjugated lipid in the SNALP formulations in Patent ‘435 are the same or essentially the same (comprising 1:57 and/or 1:62 see col.5 lines 56-67 and 6 lines 15-30) formulations since they disclose the same process of making that would naturally result in the SNALP having the claimed morphological property of being at least about 95% electron dense as in the instant claims. Thus the morphology limitation of claim 1 is inherently disclosed by Patent ‘435 as described above. A limitation is inherent if it is the “natural result flowing from” the prior art’s explicit disclosure. Id. at 1379. A patent “can be invalid based on inherency when the patent itself makes clear that a limitation is ‘not an additional requirement imposed by the claims . . . but rather a property necessarily present’.” Hospira, Inc. v. Fresenius Kabi USA, LLC, 946 F.3d 1322, 1332 (Fed. Cir. 2020) (quoting In re Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009)).
With respect to claims 2-5 claiming siRNA, the instant specification defines the nucleic acid as a siRNA with modifications (see 0014 and 0017). “The specification can be used as a dictionary to learn the meaning of a term in the claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999) ("[W]ords in patent claims are given their ordinary meaning in the usage of the field of the invention, unless the text of the patent makes clear that a word was used with a special meaning.")”. Thus the instant application and Patent ‘668 have overlapping scope for the nucleic acid molecule.
Patent ‘668 does not claim the cationic lipid comprises three or more fatty acid or fatty alkyl chains. Lee et al. and Gaucheron et al. (cited above) teach cationic lipids that contain four alkyl chains (see Scheme 1 page 673) and demonstrates a nucleic acid-lipid conjugate comprising plasmid DNA and a cationic lipid comprising four alkyl chains had higher transfection efficiency than a cationic lipid with a single alkyl chain (see Figure 4). It would have therefore been obvious to try adding three or more fatty alkyl to the cationic lipid of Patent ‘467 to improve the shape of the cationic lipid to facilitate more efficient intracellular delivery.
Patent ‘668 does not claim the cationic lipid is a titratable cationic lipid. Heyes, James, et al. ("Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids." Journal of controlled release 107.2 (2005): 276-287 cited on 892 mailed 04/21/2025) teach the use of cationic lipids with pH titratable head groups and teach the advantage of using a titratable head group allows for the cationic charge that facilitates fusion with the anionic lipid containing the endosomal bilayer (see page 284 second para).
Patent ‘668 does not teach the diastereomeric excess is less than about 55%. Lee et al. (cited above) teach a nucleic acid lipid particle is enriched in one diastereomer, such that the cationic lipid comprises at least about 55% diastereomeric excess (see 0267 page 82). It would therefore have been obvious to enrich the lipid with one diastereomer with at least about 55% diastereomeric excess as taught by Lee et al.
Thus the claims are not patentably distinct.
Response to Arguments
Applicant argues Gaucheron's introductory statements foreshadow that the reference does not teach or suggest with reasonable predictability that increasing the number of fatty alkyl chains in a cationic lipid will necessarily or reliably result in improved transfection efficiency or any other property relevant to the pending claims. The Gaucheron Introduction Section reveals an unsettled and exploratory field, not a body of established knowledge from which one of ordinary skill could predictably derive the claimed invention.
This argument is not persuasive. Gaucheron et al. is directly related to cationic lipids and the issues faced regarding delivery to cells. This is not considered an unsettled and exploratory field as argued by Applicant.
Applicant next argues Gaucheron's experimental results further illustrate the unpredictability and challenges associated with the modified cationic lipids disclosed therein, casting significant doubt on their practical utility and undermining any assertion that their teachings would have been reasonably expected to succeed when combined with the teachings of Yaworski.
This argument is not persuasive. Gaucheron et al. directly states In this work we describe the synthesis and transfection properties of a new class of cationic lipids that contain four alkyl chains. It is shown that these cationic lipids can exhibit improved transfection properties compared to dialkyl cationic lipids (page 671). This statement alone would motivate one of skill in the art to try adding more alkyl chains to a cationic lipid to improve transfection properties. One of skill in the art would have reasonably expected to be capable increasing the number of alkyl chains in the cation lipid taught by Yaworski.
Applicant next argues Gaucheron's introduction of tetraalkyl cationic lipids did not consistently, or even generally, result in improved transfection efficiency or other functional benefits over standard cationic lipids. In particular, Gaucheron's comparative studies between TODMAC3, TODMAC6, and DODAC demonstrate that, under most tested conditions, the modified tetraalkyl cationic lipids failed to outperform the conventional DODAC lipid.
Applicants argues are taken out of context and do not describe the entire results. Gaucheron et al. teach cationic lipids with tethers three and six carbons long TODMAC3 and TODMAC6, respectively and demonstrates the transfection properties of complexes formed in this manner along with DODAC, as shown in Figure 4. Gaucheron et al. found It may be noted that at charge ratios of two and lower DODAC exhibits superior transfection properties; however, at charge ratios above two TODMAC6 exhibits transfection properties that are superior to both DODAC and TODMAC3. Specifically, for charge ratios g2.5, TODMAC6 complexes gave rise to luciferase expression levels 5-20-fold higher than could be achieved with DODAC or TODMAC3. Thus it is clear that using cationic lipids with three or more alkyl chains can have higher expression levels. One of skill in the would clearly have been motivated to try adding addition alkyl chains of the cationic lipid of Yaworski to try and improve transfection properties. There is a finite number of alkyl chains that can be added, such as three, with a reasonable expectation that some level of improvement would occur based on the teaching of Gaucheron et al.
Applicant argues Gaucheron's TODMAC3 results contradict its own hypothesis and this disconnect between the hypothesized structure-function relationship and the observed experimental outcomes exposes a fundamental unpredictability in the field and demonstrates that the molecular shape rationale advanced by Gaucheron is not a reliable or enabling technical teaching.
This argument is not persuasive. Whether or not a prior art’s hypothesis on the outcome of an experimental result has nothing to do with what is actually shown in the reference. As stated above, it is clear that using cationic lipids with three or more alkyl chains can have higher expression levels. One of skill in the would clearly have been motivated to try adding addition alkyl chains of the cationic lipid of Yaworski to try and improve transfection properties. There is a finite number of alkyl chains that can be added, such as three, with a reasonable expectation that some level of improvement would occur based on the teaching of Gaucheron et al.
Applicant argues Gaucheron’s data highlights practical drawbacks because reliance on high charge ratios to achieve its only instances of modest improvement therefore highlights a further practical drawback.
This argument is not persuasive because firstly, the instant claims do not recite any limitation regarding charge ratios and the reference is not relied upon for that teaching. Further, Applicant appears to continually ignore what the data actually shows: charge ratios above two TODMAC6 exhibits transfection properties that are superior to both DODAC and TODMAC3. Specifically, for charge ratios g2.5, TODMAC6 complexes gave rise to luciferase expression levels 5-20-fold higher than could be achieved with DODAC or TODMAC3. Thus it is clear that using cationic lipids with three or more alkyl chains can have higher expression levels. One of skill in the would clearly have been motivated to try adding additional alkyl chains of the cationic lipid of Yaworski to see if they could improve transfection properties. There is a finite number of alkyl chains that can be added, such as three, with a reasonable expectation that some level of improvement would occur based on the teaching of Gaucheron et al.
Applicant next argues the Examiner's reliance on Gaucheron Figure 4 as a basis to modify Yaworski is misplaced because the formulations underlying Figure 4 are not technically relevant to the compositions required by Yaworski or the pending claims.
Applicant is arguing against limitations that are not claimed. There is nothing in the claimed invention that describes specific formulations that can be used. Gaucheron et al. was relied upon for a motivation to try using more alkyl chains to see if the transfection efficiency can be improved with a reasonable expectation of success. One of skill in the would clearly have been motivated to try adding additional alkyl chains of the cationic lipid of Yaworski to see if they could improve transfection properties. There is a finite number of alkyl chains that can be added, such as three, with a reasonable expectation that some level of improvement would occur based on the teaching of Gaucheron et al.
Applicant argues the references of Gaucheron et al. and Yaworski are not properly combinable. Applicant’s argument is fundamentally untrue because Gaucheron et al. is a prior art reference in the field of cationic lipids and ways to improve delivery and states DNA-cationic lipid complexes are the leading nonviral gene therapy vectors used in the clinical setting (1-4). However the levels of gene expression that can be achieved using these complexes are substantially lower than can be achieved using viral vectors. Considerable effort has therefore been devoted to synthesizing new cationic lipids that have improved transfection properties over those currently available. This statement alone would lead one of skill in the art to look for ways to improve transfection of the nucleic acid lipid complex taught in Yaworski and further would lead one of skill in the art to try adding additional alkyl chains based on the results demonstrated by Gaucheron et al.
Applicant goes on to argue that Gaucheron describes different types of lipid-based vehicles, the experiments are conducted exclusively in vitro and is concerned with permanently charged cationic lipids. In response, these arguments are not persuasive and would not prevent one of skill in the art to acknowledge that the results show using more alkyl chains to increase the transfection efficiency of a cationic lipid. One of skill in the art would look for ways to improve transfection of the nucleic acid lipid complex taught in Yaworski and further would lead one of skill in the art to try adding additional alkyl chains based on the results demonstrated by Gaucheron et al.
Thus in the absence of evidence to the contrary, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
Applicant further argues the Double Patenting rejections against 12,129,467, 9,364,435 and 8,822,668 based on the arguments against Gaucheron as well as Heyes et al. The Examiner’s arguments would apply to the use of Gaucheron here ss argued above. One of skill in the would clearly have been motivated to try adding additional alkyl chains of the cationic lipid of Yaworski to see if they could improve transfection properties.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kimberly Chong at (571)272-3111. The examiner can normally be reached Monday thru Friday between M-F 8:00am-4:30pm.
If attempts to reach the examiner by telephone are unsuccessful please contact the SPE for 1636 Neil Hammell at 571-272-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public. For more information about the PAIR system, see http://pair-direct.uspto.gov.
For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199.
/KIMBERLY CHONG/
Primary Examiner Art Unit 1636