Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed August 21, 2025.
Amendments
Applicant's amendments, filed August 21, 2025, is acknowledged. Applicant has cancelled Claims 1-50, 54-55, 61, 63-70, and 74-77, amended Claims 51-52, 58, and 71-72, and added new claims, Claim 78.
Claims 51-53, 56-60, 62, 71-73, and 78 are pending and under examination.
Priority
This application is a continuation of application 15/495,157 filed on April 24, 2017, now abandoned, which is a continuation of application 14/790,562 filed on July 2, 2015, now U.S. Patent 9,668,980. Acknowledgement is also made to prior application 15/979,054, filed April 24, 2017, which is also a continuation of application 14/790,562. Applicant’s claim for the benefit of a prior-filed application provisional application 62/020,163 filed on July 2, 2014 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/020,163 filed on July 2, 2014 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the pa-tent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in [provisional application]. Thus, [provisional application] do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
With respect to Claim 51, Applicant has amended the claim to recite “wherein the flow rate at which the buffered mRNA solution is mixed is at least 4X greater than the flow rate of the lipid solution to yield a suspension of 15-25% ethanol comprising lipid nanoparticles encapsulating the mRNA”.
Applicant argues support for which is found in Figure 1, per Example 2, which the Examiner finds persuasive, in part.
Figure 1 discloses the mRNA solution flow rate is 200ml/min when mixed with the lipid solution flow rate of 50ml/min.
However, instantly recited mRNA solution and lipid solution flow rates are far broader in scope than that illustrated in Figure 1, for which the originally filed specification fails to disclose blazemarks of the 4X limitation as it pertains to the other flow rate values, concordantly and respectively.
As discussed previously, Example 1 fails to disclose the relative rates of the mRNA solution mixed into the lipid solution. Rather, the Example merely states “was injected rapidly”.
One simply cannot discern the resulting relative ratio by which the aqueous buffered mRNA solution was mixed into the lipid solution from such obfuscation.
‘163 Example 2 disclosed the buffered mRNA solution was mixed with the ethanolic lipid solution at a relative mixing rate of 200ml/min mRNA: 50ml/min ethanolic lipid, which is 4X, as illustrated in Figure 1.
There are no blazemarks to select 4X relative flow rates as it pertains to the broader genus of mRNA solution flow rates relative to the broader genus of lipid solution flow rates, concordantly and respectively.
The Examiner notes that Claim 51 recites “at least 4X”, which is open-ended, having no upper limit. However, Figure 1 and Example 2 disclose 4X, not greater than 4X.
There are no blazemarks to select a genus of greater than 4X relative flow rates, including as much as 200X, as it pertains to the broader genus of mRNA solution flow rates relative to the broader genus of lipid solution flow rates, concordantly and respectively.
Example 2 discloses a buffered mRNA solution/lipid solution in 20% ethanol.
There are no blazemarks for the instantly recited broader range of 15-25% ethanol.
[0031] discloses “about” is +/- 25%.
Instant independent Claim 52 encompasses method step parameters of:
i) a mRNA solution temperature ranging from 16C to 78C;
ii) an mRNA solution flow rate ranging from 115 to 6250ml/min;
iii) a lipid solution temperature ranging from 16C to 78C;
iv) a lipid solution flow ranging rate from 19-1250ml/min;
v) mixing mRNA solution and lipid solution at a temperature ranging from 16C to 78C;
vi) a mRNA solution flow rate:lipid solution flow rate ranging from 4X-200X; and
vii) a buffered mRNA solution/lipid solution in 15-25% ethanol.
Applicant previously argued that the ordinary artisan would understand that the inherent cap for the temperature limitation would be about 78C, which is the boiling point of ethanol.
Such combinations of method step parameters are broader in scope than Figure 1 and Example 2.
There are no blazemarks to select the combination and/or subcombinations of each of the (i), (ii), (iii), (iv), (v), (vi), and (vii) method step parameters, concordantly and respectively, recited in the claim.
Rather, at best, Figure 1 and Example 2 disclose method step parameters of:
i) a mRNA solution temperature of 65C;
ii) an mRNA solution flow rate of 200ml/min;
iii) a lipid solution temperature of 65C;
iv) a lipid solution flow rate of 50ml/min;
v) mixing mRNA solution and lipid solution at a temperature of 65C;
vi) a mRNA solution flow rate:lipid solution flow rate is 4X; and
vii) a buffered mRNA solution/lipid solution in 20% ethanol.
With respect to Claim 52, Applicant has amended the claim per the ‘163 working example [0115] disclosing that the mRNA stock solution comprises a mRNA concentration of about 1mg/ml, which the Examiner finds persuasive.
With respect to Claim 58, Applicant argues support for the amended claim is found in Figure 1 (8.86mg/ml), which the Examiner finds persuasive.
With respect to Claims 71, Applicant argues that Figure 1 and Example 2 used gear pumps, which provides pulse-less flow, which the Examiner finds persuasive.
With respect to Claim 72, Applicant has amended the claim per the ‘163 working example disclosing that mixing the aqueous buffered mRNA solution and the lipid solution yielded a 20% ethanol solution (e.g. [0119], “to yield a final suspension in 20% ethanol”), which the Examiner finds persuasive.
United States Court of Appeals for the Federal Circuit, FWP IP APS v. Biogen MA, Inc (Case 2017-2109; decided October 24, 2018).
Piecing together elements of several claims and/or disparate portions of the specification to arrive at the specifically claimed subject matter does not satisfy the written description requirement. The task of locating the now-claimed subject matter within the original claims is made uncommonly more difficult by the original claims themselves, which are written in a cascading, multiple dependencies manner such that many of them generically refer back to any one of the preceding claims. Title 35 forbids this type of claim drafting because it can—as here—lead to bizarrely complex chains of cross-referencing claims in which one multiple depedent claim impermissibly serves as a basis for other multiple dependent claims. Finding the presently recited combination of specific experimental parameters, including the specific combination of disparate subgenus experimental parameters “in the morass of possible combinations of the impermissibly-drafted original claims would-- as Judge Learned Hand
observed in a different but related context—take “the patience of a yogi to decipher their meaning, as they stand.” Victor Talking Mach. Co. v. Thomas A. Edison, Inc., 229 F. 999, 1001 (2d Cir. 1916). A review of the claims and their intermixing dependencies presents an overall picture of a set of claims designed to preempt a conspicuously large number of different dosage regimens for a large variety of conditions using a long list of formulations, which is disconnected from a written description that is far more limited in its disclosure.
The disclosure of 62/020,163 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the claims of the instant application.
The disclosures of 14/790,562 filed on July 2, 2015 and 15/495,157 filed on April 24, 2017, having the same specification as ‘163, are similarly deficient.
Originally presented claims in 62/020,163, 14/790,562, and 15/495,157 suffer from impermissible multiple dependent claims.
Accordingly, the effective priority date of the Claim 52 is granted as the filing date of the instant application, December 1, 2021.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Response to Arguments
Applicant argues for the specification of provisional 62/020163 provides support for the presently amended claims, citing paragraphs and claims of the provisional application.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner has amended the above explanations for denial of priority pertaining to the amended claim set.
Applicant argues for the specification of provisional 62/020163 provides support for the presently amended claims, citing paragraphs and claims of the provisional application.
Applicant’s argument(s) has been fully considered, but is not persuasive. As discussed above, the originally filed specification(s) and claims do not satisfy the written description requirements of the presently recited combination of claimed method step parameters for reasons set forth in United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023) and United States Court of Appeals for the Federal Circuit, FWP IP APS v. Biogen MA, Inc (Case 2017-2109; decided October 24, 2018).
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.
1. Claims 51-53, 56-60, 62, 71-73, and 78 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has amended Claim 51 to recite “wherein the flow rate at which the buffered mRNA solution is mixed is at least 4X greater than the flow rate of the lipid solution to yield a suspension of 15-25% ethanol comprising lipid nanoparticles encapsulating the mRNA”.
Applicant argues support for which is found in Figure 1, per Example 2, which the Examiner finds persuasive, in part.
Figure 1 discloses the mRNA solution flow rate is 200ml/min when mixed with the lipid solution flow rate of 50ml/min.
However, instantly recited mRNA solution and lipid solution flow rates are far broader in scope than that illustrated in Figure 1, for which the originally filed specification fails to disclose blazemarks of the 4X limitation as it pertains to the other flow rate values, concordantly and respectively.
As discussed previously, Example 1 fails to disclose the relative rates of the mRNA solution mixed into the lipid solution. Rather, the Example merely states “was injected rapidly”.
One simply cannot discern the resulting relative ratio by which the aqueous buffered mRNA solution was mixed into the lipid solution from such obfuscation.
‘163 Example 2 disclosed the buffered mRNA solution was mixed with the ethanolic lipid solution at a relative mixing rate of 200ml/min mRNA: 50ml/min ethanolic lipid, which is 4X, as illustrated in Figure 1.
There are no blazemarks to select 4X relative flow rates as it pertains to the broader genus of mRNA solution flow rates relative to the broader genus of lipid solution flow rates, concordantly and respectively.
The Examiner notes that Claim 51 recites “at least 4X”, which is open-ended, having no upper limit. However, Figure 1 and Example 2 disclose 4X, not greater than 4X.
There are no blazemarks to select a genus of greater than 4X relative flow rates, including as much as 200X, as it pertains to the broader genus of mRNA solution flow rates relative to the broader genus of lipid solution flow rates, concordantly and respectively.
Example 2 discloses a buffered mRNA solution/lipid solution in 20% ethanol.
There are no blazemarks for the instantly recited broader range of 15-25% ethanol.
[0031] discloses “about” is +/- 25%.
Instant independent Claim 52 encompasses method step parameters of:
i) a mRNA solution temperature ranging from 16C to 78C;
ii) an mRNA solution flow rate ranging from 115 to 6250ml/min;
iii) a lipid solution temperature ranging from 16C to 78C;
iv) a lipid solution flow ranging rate from 19-1250ml/min;
v) mixing mRNA solution and lipid solution at a temperature ranging from 16C to 78C;
vi) a mRNA solution flow rate:lipid solution flow rate ranging from 4X-200X; and
vii) a buffered mRNA solution/lipid solution in 15-25% ethanol.
Applicant previously argued that the ordinary artisan would understand that the inherent cap for the temperature limitation would be about 78C, which is the boiling point of ethanol.
Such combinations of method step parameters are broader in scope than Figure 1 and Example 2.
There are no blazemarks to select the combination and/or subcombinations of each of the (i), (ii), (iii), (iv), (v), (vi), and (vii) method step parameters, concordantly and respectively, recited in the claim.
Rather, at best, Figure 1 and Example 2 disclose method step parameters of:
i) a mRNA solution temperature of 65C;
ii) an mRNA solution flow rate of 200ml/min;
iii) a lipid solution temperature of 65C;
iv) a lipid solution flow rate of 50ml/min;
v) mixing mRNA solution and lipid solution at a temperature of 65C;
vi) a mRNA solution flow rate:lipid solution flow rate is 4X; and
vii) a buffered mRNA solution/lipid solution in 20% ethanol.
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in [62/020,163]. Thus, [62/020,163] do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
United States Court of Appeals for the Federal Circuit, FWP IP APS v. Biogen MA, Inc (Case 2017-2109; decided October 24, 2018).
Piecing together elements of several claims and/or disparate portions of the specification to arrive at the specifically claimed subject matter does not satisfy the written description requirement. The task of locating the now-claimed subject matter within the original claims is made uncommonly more difficult by the original claims themselves, which are written in a cascading, multiple dependencies manner such that many of them generically refer back to any one of the preceding claims. Title 35 forbids this type of claim drafting because it can—as here—lead to bizarrely complex chains of cross-referencing claims in which one multiple depedent claim impermissibly serves as a basis for other multiple dependent claims. Finding the presently recited combination of specific experimental parameters, including the specific combination of disparate subgenus experimental parameters “in the morass of possible combinations of the impermissibly-drafted original claims would-- as Judge Learned Hand
observed in a different but related context—take “the patience of a yogi to decipher their meaning, as they stand.” Victor Talking Mach. Co. v. Thomas A. Edison, Inc., 229 F. 999, 1001 (2d Cir. 1916). A review of the claims and their intermixing dependencies presents an overall picture of a set of claims designed to preempt a conspicuously large number of different dosage regimens for a large variety of conditions using a long list of formulations, which is disconnected from a written description that is far more limited in its disclosure.
The disclosure of 62/020,163 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the claims of the instant application.
The disclosures of 14/790,562 filed on July 2, 2015 and 15/495,157 filed on April 24, 2017, having the same specification as ‘163, are similarly deficient.
Originally presented claims in 62/020,163, 14/790,562, and 15/495,157 suffer from impermissible multiple dependent claims.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The specification fails to disclose a nexus between the required method step parameters of independent Claim 51:
the mRNA solution working concentration (generic; range 0.1 to 100mg/ml, or more, no upper limit);
the lipid solution working concentration (generic; range 0.1 to 100mg/ml, or more, no upper limit);
the lipid solution temperature (range 25-70C);
the mRNA solution pH value (generic, no upper or lower limit);
the relative mRNA:lipid mixing rate (range 4X to 200X (5000ml/min: 25ml/min)); and/or
the mRNA solution temperature (range 25-78C);
individually and/or in combination and/or subcombinations thereof,
whereupon said method is further limited to:
a mRNA stock solution comprises mRNA at a concentration greater than 1mg/ml (Claim 52);
wherein the lipid solution has a total concentration of about 9mg/ml (Claim 58);
wherein the mRNA solution and lipid solution are mixed by a pulse-less flow pump (Claims 71 and 78); and/or
wherein the mRNA solution and the lipid solution are mixed to yield a 20% ethanol solution (Claim 72);
individually and/or in combination and/or subcombinations thereof.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
Response to Arguments
Applicant argues that the instant inventions are discussed extensively throughout the specification.
Applicant’s argument(s) has been fully considered, but is not persuasive. As discussed above, Example 1 fails to disclose thus-prepared aqueous buffered mRNA solution is the “stock” solution, nor that the thus-prepared aqueous buffered mRNA solution has a concentration equal to or greater than 1mg/ml. Rather, it is the un-buffered mRNA stock solution that has a concentration of 1mg/ml. The Example obfuscates the actual working mRNA concentration in the aqueous buffered solution.
The ‘163 working examples are silent to the total lipid concentration of the heated lipid solution. While it appears that each of the four lipid stock solutions have a concentration of 50mg/ml, the examples fail to disclose the volume of the “aliquot” used from each of the respective lipid stock solutions to then be diluted in the 3ml of ethanol. One simply cannot discern the resulting total lipid concentration from such obfuscation.
‘163 Example 1 fails to disclose the relative rates of the mRNA solution mixed into the lipid solution. Rather, the Example merely states “was injected rapidly”. One simply cannot discern the resulting relative ratio by which the aqueous buffered mRNA solution was mixed into the lipid solution from such obfuscation. At best, one must look to Example 2 disclosing the buffered mRNA solution was mixed with the ethanolic lipid solution at a relative mixing rate of 200ml/min mRNA: 50ml/min ethanolic lipid, which is 4X.
Rather, Applicant appears to be picking and choosing disparate disclosures to argue support of the instantly claimed inventions, for which there are no sufficient blazemarks to guide the skilled artisan to the instant claims.
Applicant argues for the specification of provisional 62/020163 provides support for the presently amended claims, citing paragraphs and claims of the provisional application.
Applicant’s argument(s) has been fully considered, but is not persuasive. As discussed above, the originally filed specification(s) and claims do not satisfy the written description requirements of the presently recited combination of claimed method step parameters for reasons set forth in United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023) and United States Court of Appeals for the Federal Circuit, FWP IP APS v. Biogen MA, Inc (Case 2017-2109; decided October 24, 2018).
Claim Rejections - 35 USC § 102
2. The prior rejection of Claim(s) 51, 56, 59-60, 62, and 71-73 under 35 U.S.C. 102(a)(1) and/or under 35 U.S.C. 102(a)(2) as being anticipated by MacLachlan et al (US 2007/0042031; of record) is withdrawn in light of Applicant’s amendment to the independent claim to recite a nucleic acid solution:lipid solution relative flow rate of at least 4X, a limitation MacLachlan et al do not disclose. MacLachlan et al’s working examples disclose a nucleic acid solution:lipid solution relative flow rate of 1X (e.g [0092-93], tables).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
3. The prior rejection of Claims 51-53, 56-60, 62, and 71-73 under AIA 35 U.S.C. 103 as being unpatentable over MacLachlan et al (US 2007/0042031; of record) in view of Guild et al (2011/0244026; Applicant’s own work; of record) is withdrawn in light of Applicant’s amendment to the independent claim to recite a nucleic acid solution:lipid solution relative flow rate of at least 4X, a limitation neither MacLachlan et al nor Guild et al disclose.
4. Claims 51-53, 56-60, 62, 71-73, and 78 are rejected under AIA 35 U.S.C. 103 as being unpatentable over MacLachlan et al (US 2007/0042031; of record) in view of Guild et al (2011/0244026; Applicant’s own work; of record), Justo et al (2011; of record), and Knopov et al (WO 01/05373; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 51, MacLachlan et al is considered relevant prior art for having disclosed a method of encapsulating the artisan’s nucleic acid of interest in lipid nanoparticles, wherein the nucleic acid may be DNA, oligonucleotide, mRNA, or antisense RNA [0021].
MacLachlan et al disclosed wherein the lipid solution comprises:
a PEG-modified lipid, e.g. PEG-C-DMA;
helper lipids cholesterol and DSPC; and
cationic lipid DlinDMA (Example 1, [0088]).
MacLachlan et al disclosed wherein the lipids are dissolved in an ethanolic solution (e.g. [0040, 46]).
MacLachlan et al disclosed wherein the RNA is in a buffered solution, pH 5 comprising 20mM citrate buffer ([0058]; Example 2, Table).
MacLachlan et al disclosed wherein the nucleic acid solution and the lipid solutions are mixed at a flow rate of 200ml/min or 400ml/min (Example 1; Example 2, Table), which thus reads upon the instantly recited mRNA solution flow rate of at least 150ml/min and the instantly recited lipid solution flow rate of at least 25ml/min.
MacLachlan et al disclosed a relative mRNA:lipid mixing rate of 1X.
MacLachlan et al disclosed wherein the solutions are at room temperature (e.g. [0058]; [0079], “lipid vesicles are typically formed at room temperature, but lipid vesicles may be formed at elevated temperatures”).
Those of ordinary skill in the art understand room temperature to mean 25C, which is greater than instant recitation of ambient temperature being about 20C.
Furthermore, the disclosure that “the lipid vesicles may be formed at elevated temperatures” would be understood by the ordinary artisan to greater than room temperature 25C.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
MacLachlan et al disclosed wherein the lipid and nucleic acid solution are mixed to yield a 20% ethanol solution (e.g. [0053], “vesicles are formed in a high alkanol (e.g. ethanol) environment (e.g. about 20%)”; [0054]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
MacLachlan et al do not disclose a working example whereby the nucleic acid solution mixed with the lipid solution is a mRNA solution.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 51, Guild et al disclosed a method of encapsulating mRNA in lipid nanoparticles, the method comprising the step(s) of:
a) mixing a buffered mRNA solution and a lipid solution,
wherein the buffered mRNA solution comprises an mRNA stock solution and a buffer having a concentration of about 10 mM or greater, and
wherein the buffered mRNA solution and the lipid solution are at a predetermined temperature above an ambient temperature of about 20-25C, to wit, 70°C (Example 1, [0099-101]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Guild et al disclosed wherein the lipid solution comprises:
one or more cationic lipids;
one or more helper lipids; and
one or more PEG-modified lipids (Example 1, [0099]).
Guild et al disclosed an example wherein the buffer solution is a citrate buffer (Example 1, [0100]).
MacLachlan et al disclosed wherein the nucleic acid solution and the lipid solutions are mixed at a flow rate of 200ml/min or 400ml/min (Example 1; Example 2, Table), which thus reads upon the instantly recited mRNA solution flow rate of at least 150ml/min and the instantly recited lipid solution flow rate of at least 25ml/min.
Guild et al disclosed the lipid solution is injected rapidly into the aqueous mRNA solution (e.g. Example 7, [0119]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Neither MacLachlan et al nor Guild et al disclose wherein the mRNA solution is mixed with the lipid solution at a rate of at least 4X greater than the rate of the heated lipid solution.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 51, Justo et al is considered relevant prior art for having taught methods of making liposomes comprising the step(s) of:
i) heating an ethanolic lipid solution to different temperatures, e.g. 30C, 40C, 50C, 60C to improve the solubility of the lipids in the ethanolic solution (e.g. pg 787, col. 1, Methods, 2.2.2. Liposome production; Figure 1);
ii) heating an aqueous solution to different temperatures, e.g. 30C, 40C, 50C, 60C (e.g. pg 787, col. 1, Methods, 2.2.2. Liposome production; Figure 1); and
iii) mixing the heated ethanolic lipid solution and the heated aqueous solution to generate a suspension of lipid nanoparticles.
Justo et al taught wherein the aqueous solution comprises a 300mM citrate buffer, pH 4.0.
Justo et al taught wherein the aqueous solution is mixed at a ratio of at least 3X greater than the ethanolic lipid solution (e.g. 76 volumes aqueous, 4 volumes ethanolic lipid = 19X).
Similarly, Knopov et al is considered relevant prior art for having disclosed a method of making lipid nanoparticles, the method comprising the step(s) of:
i) formulating a lipid solution in an ethanolic solvent;
ii) formulating an aqueous solution comprising a buffer; and
iii) mixing the lipid solution with the aqueous buffer to form lipid nanoparticles, wherein the aqueous buffer solution flow rate is at least 6X or 10X greater than the flow rate of the lipid solution (pgs 18-19, Example 1, aqueous buffer (mainstream) flow rate = 4400ml/min and lipid/ethanol (side stream) flow rate = 775ml/min, 4400/775 = 5.7x; Example 2, aqueous buffer flow rate = 3200-5800ml/min and lipid/ethanol flow rate = 320-990ml/min, 5800/990 = 6X
3200/320 = 10X).
Knopov et al disclosed wherein the aqueous buffered solution comprises the artisan’s nucleic acid of interest, e.g. therapeutic oligonucleotides, to be encapsulated in the thus-produced liposomes (e.g. pg 16, lines 19-22, “encapsulated within the lipid particle”).
Knopov et al disclosed an example wherein the buffered mRNA solution has a concentration of 10mM or greater, e.g 300mM citrate buffer, pH 4.0 (pg, 5, line 14; pg 18, Example 2, lines 29-30).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Knopov et al disclosed wherein the aqueous solution comprises a citrate buffer (pg, 5, line 14, “standard liposome buffer”; pg 18, Example 2, lines 29-30).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, nucleic acid delivery vehicles, and methods of making lipid nanoparticles. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute the siRNA nucleic acid solution, as disclosed by MacLachlan et al, with a mRNA nucleic acid solution, as taught/disclosed by MacLachlan et al and Guild et al, in a method of encapsulating mRNA in lipid nanoparticles with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute the siRNA nucleic acid solution with a mRNA nucleic acid solution in a method of encapsulating mRNA in lipid nanoparticles because MacLachlan et al disclosed the nucleic nucleic acid may be DNA, siRNA, or mRNA, and Guild et al (Applicant’s own work) had successfully demonstrated the ability of the ordinary artisan to successfully encapsulate mRNA in lipid nanoparticles.
Prior to the effective filing date of the instantly claimed invention, it also would have been obvious to one of ordinary skill in the art to modify the method of MacLachlan et al mixing the lipid solution and the nucleic acid aqueous solution to form lipid nanoparticles to comprise the step of mixing the mRNA lipid solution with the lipid solution at a rate of at least 3X greater than the rate of the lipid solution with a reasonable expectation of success because Justo et al taught the aqueous solution is mixed at a ratio of at least 3X greater than the ethanolic lipid solution (e.g. 19X), and Knopov et al successfully demonstrated the ability to synthesize lipid nanoparticles comprising the step of mixing an aqueous solution with a lipid solution to form lipid nanoparticles, wherein the aqueous solution is mixed at a rate of at least 5.7X, 6X, or 10X greater than the rate of the lipid solution.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claims 56 and 59, MacLachlan et al disclosed wherein the one or more helper lipids include DSPC (e.g. [0029]; Example 1), which is an art-recognized zwitterionic lipid.
Guild et al disclosed wherein the one or more helper lipids comprise non-cationic lipids and cholesterol-based lipids (e.g. [0099]). Guild et al disclosed wherein the one or more helper lipids include DSPC, DOPC, DPPC, DOPE, POPC, POPE, DPPE, DMPE, DSPE, and combinations thereof [0062], whereby said phosphatidylcholine (PC) and phosphatidylethanolamine (PE) headgroups present in DSPC, DOPC, DPPC, DOPE, POPC, POPE, DPPE, DMPE, and/or DSPE are art-recognized zwitterionic lipids.
With respect to Claim 60, MacLachlan et al disclosed wherein the one or more PEG-modified lipid is PEG-C-DMA (e.g. [0017]; pg 83, lines 1-3). Sun et al (2023; of record) evidences that the art recognizes PEG-C-DMA to comprise a poly(ethylene)glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length (Figure 8d).
Guild et al disclosed wherein the one or more PEG-modified lipids comprise a poly(ethylene)glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length (e.g. [0061]).
With respect to Claim 62, MacLachlan et al disclosed wherein the therapeutic nucleic acid may comprise modified nucleotides (e.g. [0020, 22]).
Guild et al disclosed wherein the mRNA comprises one or more modified nucleotides (e.g. [0035-42]).
With respect to Claims 71 and 78, MacLachlan et al disclosed wherein the nucleic acid and lipid solutions are mixed using a pulse-less flow pump (e.g. [0079], “pulseless gear pump”).
With respect to Claim 72, MacLachlan et al disclosed wherein the lipid and nucleic acid solution are mixed to yield a 20% ethanol solution (e.g. [0053], “vesicles are formed in a high alkanol (e.g. ethanol) environment (e.g. about 20%)”; [0054]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
With respect to Claim 73, MacLachlan et al disclosed wherein the lipid nanoparticles are purified using tangential flow filtration (e.g. [0062]).
Knopov et al disclosed wherein the lipid nanoparticles may be purified using TFF (e.g. pg 8, lines 14-15).
With respect to Claim 52, the Examiner notes that the ‘163 disclosure states “was prepared from a 1mg/ml stock”. While it is clear that an mRNA stock solution of 1mg/ml was used to then make another buffered mRNA solution, the examples fail to actually disclose the mRNA concentration in the aqueous buffered solution that is heated and mixed with the heated lipid solution. Rather, the thus-obtained encapsulated mRNA concentration is only about 0.20mg/ml. Table 1 discloses an encapsulation efficiency ranging from 80% to 96%, and thus the actual working mRNA concentration in the heated aqueous buffered solution that is mixed with the heated lipid solution to form the lipid nanoparticles is estimated to only be at about 0.25mg/ml.
The claims fail to recite the actual concentration of the mRNA in the heated mRNA solution that is to be mixed with the heated lipid solution to produce the thus-formed the lipid nanoparticles.
Thus, as it pertains to the heated mRNA solution that is to be mixed with the heated lipid solution, the recitation of the mRNA stock solution having a concentration of 1mg/ml or greater may be interpreted as a product-by-process recitation.
The recitation of a process limitation in Claim 52 is not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claim 52 imparts a novel or unexpected property to the claimed product, as it is assumed that equivalent products of, e.g. a heated aqueous buffered mRNA solution having a concentration of 0.01mg/ml, 0.05mg/ml, 0.1mg/ml, 0.25mg/ml, 0.5mg/ml, etc.. mRNA are obtainable by multiple routes, to wit, mRNA stock solutions having concentrations of 1mg/ml, 5mg/ml, 10mg/ml, 20mg/ml, etc…. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the heated mRNA solution that is to be mixed with the heated lipid solution to form the lipid nanoparticles were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
The "mere existence of differences between the prior art and an invention does not establish the invention's nonobviousness." Dann v. Johnston, 425 U.S. 219, 230, 189 USPQ 257, 261 (1976). The gap between the prior art and the claimed invention may not be "so great as to render the [claim] nonobvious to one reasonably skilled in the art."Id.
Nevertheless, Guild et al disclosed an example wherein the mRNA stock solution has an mRNA concentration of 1mg/ml (Example 7, [0119]).
MacLachlan et al disclosed wherein the aqueous buffered RNA solution that is mixed with the lipid solution has an RNA concentration of 0.225mg/ml-0.9mg/ml (Example 1, [0088]; Example 2, Tables).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Applicant fails to disclose an element of criticality for the mRNA stock solution concentration to be at least 1mg/ml.
With respect to Claim 53, the specification discloses “about” to be +/- 25% of the reference value, and thus the claim encompasses a range of pH 3.375 to 5.625.
Guild et al disclosed an example wherein the buffered mRNA solution has a pH of 5.0 (Example 1, [0100]) or pH 4.5 (Example 7, [0119]).
Justo et al taught wherein the aqueous buffered solution is pH 4.0.
Knopov et al disclosed an example wherein the buffered mRNA solution has a pH of about 4.5 (pg, 5, line 14, “standard liposome buffer, (pH 4.2)”; pg 18, Example 2, lines 29-30, “pH 4.0”).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
With respect to Claim 57, Guild et al disclosed an example wherein the lipids are dissolved in absolute ethanol (Example 1, [0099], “dissolved in absolute ethanol at 70C”).
Knopov et al disclosed wherein the lipids are dissolved in absolute ethanol (pg 12, lines 1-4; Example 1, line 15, “Ethanol (100%)” (syn. absolute ethanol)).
With respect to Claim 58, MacLachlan et al disclosed wherein the lipid solution has a concentration of greater than 1mg/ml, e.g. 11-15mg/ml [0047].
Guild et al disclosed an example wherein the total lipid concentration is about 11mg/ml (Example 2, [0108]).
Knopov et al disclosed wherein the lipid solution has a concentration of 10-25mg/ml (e.g. pg 12, lines 28-31) or 2-13mg/ml (pg 17, lines 31-32).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that neither MacLachlan et al nor Guild et al disclose wherein the mixed nucleic acid/lipid solutions yield a suspension of 15-25% ethanol solution comprising the lipid nanoparticles.
Applicant’s argument(s) has been fully considered, but is not persuasive. MacLachlan et al disclosed wherein the lipid and nucleic acid solution are mixed to yield a 20% ethanol solution (e.g. [0053], “vesicles are formed in a high alkanol (e.g. ethanol) environment (e.g. about 20%)”; [0054]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Applicant iterates prior arguments.
The Examiner has responded to prior arguments in prior Office Actions.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
5. Claims 51-52 and 71-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 9,668,980.
Although the claims at issue are not identical, they are not patentably distinct from each other.
With respect to Claim 51, ‘980 claims (claims 1-4, 6-7, 10-12, and 14) a method of encapsulating mRNA into a lipid nanoparticle, wherein the mRNA solution flow rate is at least 150ml/min and the lipid solution flow rate is at least 25ml/min, and wherein the temperature is at least 25C or at least 65C.
‘980 claims an mRNA solution flow rate of up to 6000ml/min (claim 1), 600ml/min (claim 6), and 200ml/min (claims 3 and 11), and a lipid solution flow rate of 50ml/min (claims 4 and 12), which yields a relative mRNA solution flow rate of at least 4x, 12x, or 120x.
‘980 claims (claim 8) wherein the mRNA solution and lipid solution are mixed into 20% ethanol.
With respect to Claim 52, ‘980 claims (claims 5 and 13) wherein the mRNA stock solution is at least 1mg/ml.
With respect to Claim 71, ‘980 claims (claims 1 and 6) wherein the mixing is performed using a pulse-less flow pump.
With respect to Claim 73, ‘980 claims wherein the lipid nanoparticles are purified using TFF (claim 16).
‘980 claims the working experimental parameters within the claimed elements of instant Claim 51, and whereby the nucleic acid may be mRNA instead of siRNA. Thus, the recited lipid nanoparticles are considered to be inherent properties that naturally flow from the recited method steps.
Thus, the instant claims are considered to be anticipated by and/or obvious variants of the ‘980 patented claims.
Response to Arguments
Applicant argues that ‘980 does not recite a 4X flow rate ratio.
Applicant’s argument(s) has been fully considered, but is not persuasive. Claims 3 and 11 recite the mRNA solution flow rate of 200ml/min. Claims 4 and 12 recite the lipid solution flow rate of 50ml/min. Thus, the claims recite a 4X flow rate ratio, as presently claimed.
6. Claims 51, 56, 59-60, 62, 71-73, and 78 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 9,668,980, as applied to Claims 51-52 and 71-73 above, and in further view of MacLachlan et al (of record).
‘980 does not claim wherein the one or more helper lipids comprise non-cationic lipids and cholesterol-based lipids.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claims 51, 56, and 59, MacLachlan et al is considered relevant prior art for having disclosed a method of encapsulating the artisan’s nucleic acid of interest in lipid nanoparticles, wherein the nucleic acid may be DNA, oligonucleotide, mRNA, or antisense RNA [0021].
MacLachlan et al disclosed wherein the lipids are dissolved in an ethanolic solution (e.g. [0040, 46]).
MacLachlan et al disclosed wherein the RNA is in a buffered solution, pH 5 comprising 20mM citrate buffer ([0058]; Example 2, Table).
MacLachlan et al disclosed wherein the nucleic acid solution and the lipid solutions are mixed at a flow rate of 200ml/min or 400ml/min (Example 1; Example 2, Table), which thus reads upon the instantly recited mRNA solution flow rate of at least 150ml/min and the instantly recited lipid solution flow rate of at least 25ml/min.
MacLachlan et al disclosed wherein the solutions are at room temperature (e.g. [0058]; [0079], “lipid vesicles are typically formed at room temperature, but lipid vesicles may be formed at elevated temperatures”) which is understood by the ordinary artisan to mean 25C.
MacLachlan et al disclosed wherein the lipid solution comprises:
a PEG-modified lipid, e.g. PEG-C-DMA;
helper lipids cholesterol and DSPC; and
cationic lipid DlinDMA (Example 1, [0088]).
With respect to Claims 56 and 59, MacLachlan et al disclosed wherein the one or more helper lipids include DSPC (e.g. [0029]; Example 1), which is an art-recognized zwitterionic lipid.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first helper lipid, as claimed in ‘980, with a second helper lipid, e.g. a non-cationic helper lipid, as disclosed by MacLachlan et al, in a method of encapsulating mRNA in lipid nanoparticles with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first helper lipid with a second helper lipid, e.g. a non-cationic helper lipid, in a method of encapsulating mRNA in lipid nanoparticles because MacLachlan et al disclosed a genus of art-recognized helper lipids, including non-cationic helper lipids that are commonly used in the formation of lipid nanoparticles.
With respect to Claim 60, MacLachlan et al disclosed wherein the one or more PEG-modified lipid is PEG-C-DMA (e.g. [0017]; pg 83, lines 1-3). Sun et al (2023; of record) evidences that the art recognizes PEG-C-DMA to comprise a poly(ethylene)glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length (Figure 8d).
With respect to Claim 62, MacLachlan et al disclosed wherein the therapeutic nucleic acid may comprise modified nucleotides (e.g. [0020, 22]).
With respect to Claims 71 and 78, MacLachlan et al disclosed wherein the nucleic acid and lipid solutions are mixed using a pulse-less flow pump (e.g. [0079], “pulseless gear pump”).
With respect to Claim 72, MacLachlan et al disclosed wherein the lipid and nucleic acid solution are mixed to yield a 20% ethanol solution (e.g. [0053], “vesicles are formed in a high alkanol (e.g. ethanol) environment (e.g. about 20%)”; [0054]).
With respect to Claim 73, MacLachlan et al disclosed wherein the lipid nanoparticles are purified using tangential flow filtration (e.g. [0062]).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success.
Thus, the instant claims are considered to be prima facie obvious variants of the ‘980 patented claims.
Response to Arguments
Applicant argues that ‘980 does not recite wherein the buffered mRNA solution is mixed is at least 4X greater than the flow rate of the lipid solution to yield a suspension of 15-25% ethanol comprising lipid nanoparticles encapsulating the mRNA.
Applicant’s argument(s) has been fully considered, but is not persuasive. Claims 3 and 11 recite the mRNA solution flow rate of 200ml/min. Claims 4 and 12 recite the lipid solution flow rate of 50ml/min. Thus, the claims recite a 4X flow rate ratio, as presently claimed. Claim 8 recites wherein the resulting suspension of lipid nanoparticles is in a 20% ethanol solution.
7. Claims 52-53, 56-60, and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 9,668,980 in view of MacLachlan et al (of record), as applied to Claims 51-52, 56, 59-60, 62, 71-73, and 78
above, and in further view of Guild et al (2011/0244026; Applicant’s own work; of record).
While’980 claims the lipids are in an ethanol solution (e.g. claim 8), ‘980 does not claim wherein the lipids are dissolved into an absolute ethanol solution.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim 57, Guild et al disclosed an example wherein the lipids are dissolved in absolute ethanol (Example 1, [0099], “dissolved in absolute ethanol at 70C”).
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first ethanolic solution, as claimed in ‘980, to dissolve the lipids, with a second ethanolic solution, to wit, absolute ethanol to dissolve the lipids, as disclosed by Guild et al, in a method of encapsulating mRNA in lipid nanoparticles with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute a first ethanolic solution to dissolve the lipids, with a second ethanolic solution, to wit, absolute ethanol to dissolve the lipids, in a method of encapsulating mRNA in lipid nanoparticles because Applicant’s themselves previously disclosed and successfully reduced to practice the ability to dissolve the lipids in an absolute ethanol solution, thereby forming a lipid solution that is mixed with a mRNA solution to form mRNA-encapsulated lipid nanoparticles.
With respect to Claims 56 and 59, MacLachlan et al disclosed wherein the one or more helper lipids include DSPC (e.g. [0029]; Example 1), which is an art-recognized zwitterionic lipid.
Guild et al disclosed wherein the one or more helper lipids comprise non-cationic lipids and cholesterol-based lipids (e.g. [0099]). Guild et al disclosed wherein the one or more helper lipids include DSPC, DOPC, DPPC, DOPE, POPC, POPE, DPPE, DMPE, DSPE, and combinations thereof [0062], whereby said phosphatidylcholine (PC) and phosphatidylethanolamine (PE) headgroups present in DSPC, DOPC, DPPC, DOPE, POPC, POPE, DPPE, DMPE, and/or DSPE are art-recognized zwitterionic lipids.
With respect to Claim 60, MacLachlan et al disclosed wherein the one or more PEG-modified lipid is PEG-C-DMA (e.g. [0017]; pg 83, lines 1-3). Sun et al (2023; of record) evidences that the art recognizes PEG-C-DMA to comprise a poly(ethylene)glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length (Figure 8d).
Guild et al disclosed wherein the one or more PEG-modified lipids comprise a poly(ethylene)glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length (e.g. [0061]).
With respect to Claim 62, MacLachlan et al disclosed wherein the therapeutic nucleic acid may comprise modified nucleotides (e.g. [0020, 22]).
Guild et al disclosed wherein the mRNA comprises one or more modified nucleotides (e.g. [0035-42]).
With respect to Claim 52, Guild et al disclosed an example wherein the mRNA stock solution has an mRNA concentration of 1mg/ml (Example 7, [0119]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
With respect to Claim 53, the specification discloses “about” to be +/- 25% of the reference value, and thus the claim encompasses a range of pH 3.375 to 5.625.
Guild et al disclosed an example wherein the buffered mRNA solution has a pH of 5.0 (Example 1, [0100]) or pH 4.5 (Example 7, [0119]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
With respect to Claim 58, MacLachlan et al disclosed wherein the lipid solution has a concentration of greater than 1mg/ml, e.g. 11-15mg/ml [0047].
Guild et al disclosed an example wherein the total lipid concentration is about 11mg/ml (Example 2, [0108]).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success.
Thus, the instant claims are considered to be prima facie obvious variants of the ‘980 patented claims.
Citation of Relevant Prior Art
8. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kastner et al (High-throughput manufacturing of size-tuned liposomes by a new microfluidics method using enhanced statistical tools for characterization, Int. J. Pharmaceutics 477: 361-368, available online October 14, 2014) is considered relevant prior art for having taught a method of making liposomes, wherein the aqueous buffer flow rate:lipid solution flow rate varied between 1:1, 3:1, and 5:1 (syn. 1X, 3X, 5X; e.g. Figure 2), whereby as the aqueous buffer flow rate:lipid solution flow rate is increased, a reduction in liposome size was detected (e.g. pg 365, col. 2).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Belliveau et al (Microfluidic Synthesis of Highly Potent Limit-size Lipid Nanoparticles for In Vivo Delivery of siRNA, Molecular Therapy-Nucleic Acids 1: e37, 9 pages, doi:10.1038/mtna.2012.28; available online August 14, 2012) is considered relevant prior art for having taught a method of making siRNA encapsulating liposomes, wherein the siRNA aqueous buffer flow rate:lipid solution flow rate was 3:1 (syn, 3X; e.g. Figure 2, legend).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Sun et al (Structure and Function of Cationic and Ionizable Lipids for Nucleic Acid Delivery, Pharmaceutical Research 40: 27-46, 2023; of record) evidences that the art recognizes PEG-C-DMA to comprise a poly(ethylene)glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length (Figure 8d).
Srinath et al (Preparation and Pharmacodynamic Evaluation of Liposomes of Indomethacin, Drug Development & Industrial Pharmacy 26(3): 313-321, 2000; of record) is considered relevant prior art for having taught a method of making liposomes, the method comprising the step(s) of:
i) heating an ethanolic lipid solution to 50C;
ii) heating an aqueous solution to 50C; and
iii) mixing the heated aqueous solution to the heated lipid solution to generate a suspension of lipid nanoparticles (e.g. pg 315, col. 1, Methods, High-Speed Dispersion Method).
Cho et al (Improved stability of liposome in oil/water emulsion by association of amphiphilic polymer with liposome and its effect on bioactive skin permeation, Colloids and Surfaces A: Physicochem. Eng. Aspects 299: 160-168, 2007; of record) is considered relevant prior art for having taught a method of making liposomes, the method comprising the step(s) of:
i) heating an ethanolic lipid solution to 50-60C;
ii) heating an aqueous solution to 70C; and
iii) mixing the heated aqueous solution to the heated lipid solution to generate a suspension of lipid nanoparticles (e.g. pg 161, Methods, 2.2 Preparation of liposomes).
Heating the lipids to about 10C greater than the gel-to-fluid phase transition temperature of the lipids (e.g. pg 162, col. 2, Results).
Malone (Cationic liposome-mediated RNA transfection, PNAS 86: 6077-6081, 1989; of record in IDS) is considered relevant prior art for having taught encapsulation of mRNA into liposomes (DOTMA/DOPE (lipofectin).
Isele et al (Large-Scale Production of Liposomes Containing Monomeric Zinc Phthalocyanine by Controlled Dilution of Organic Solvents, J. Pharmaceutical Sciences 83(11): 1608-1616, 1994; of record in IDS) taught liposome encapsulation of an agent, the method comprising the step(s) of:
i) heating an aqueous solution comprising the desired agent to a temperature of 50C;
ii) heating a lipid solution to a temperature of 50C; and
iii) mixing the aqueous solution and the lipid solution, wherein the heated aqueous solution is mixed at a rate of 15X greater than the rate of the heated lipid solution (pg 1608, col. 2, Methods, “50C mixing temperature of organic phase with aqueous phase”; pg 1609, col. 1, Methods, Dynamic Mixing); and
iv) purifying the liposomes using cross-flow filtration (CFF; syn. tangential flow filtration) (pg 1609, col. 1, Methods, Concentration and Dialysis).
Isele et al taught wherein the mean particle size was less than 100nm (e.g. Figure 7).
Lenk et al (U.S. Patent 5,948,441; of record) is considered relevant prior art for having disclosed that those of ordinary skill in the art recognize the terms “tangential flow filtration” and “cross flow filtration” to be synonymous (col. 1, lines 24-25).
Pradhan (A Facile Microfluidic Method for Production of Liposomes, Anticancer Research 28: 943-948, 2008; of record in IDS) is considered relevant prior art for having taught a method for producing liposomes, the method comprising the step(s) of:
i) heating an aqueous solution to a temperature of 65C;
ii) heating a lipid solution to a temperature of 65C; and
iii) mixing the aqueous solution and the lipid solution, wherein the heated aqueous
(e.g pg 944, col. 1, Methods, Liposome preparation, “samples were first heated to 65C”; pg 946, col. 2, “smaller particles were generated when the temperature of the microfluidic mixing was elevated to 65C”).
Conclusion
9. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
