DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Receipt is acknowledged of Amendments, Remarks and an IDS filed on 05/08/26. Claims 1, 10-113 and 33 have been amended, claims 14-15, 18, 20-27, 29 and 32 have been cancelled and no new claims have been added. Accordingly, claims 1-13, 16-17, 19, 28, 30-31 and 33 remain pending. Claims 13, 17, 19, 28 and 30-31 remain withdrawn. Accordingly, claims 1-12, 16 and 33 remain under examination on the merits.
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Claims 1-12, 16 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Gong et al (US 20050186146).
Applicant’s claims
Claim 1 is directed to a dry powder formulation including a plurality of microparticles, the microparticles comprising: a. about 8% to about 11% leucine by weight; b. about 2% to about 4% trileucine by weight; and c. an active agent, wherein the leucine and the trileucine are present at a ratio of leucine:trileucine of about 0.1:1 to about 30:1 by weight.
Gong et al teach Interleukin-13 (IL-13) antagonist powders, spray-dried particles and a method of administering them to the lung (See Title and abstract).
Regarding claims 1, 3-7 and 9-10, Gong et al teach a dry powder formulation comprising particles with MMD of from about 0.5 micron to about 10 microns, (reading on microparticles), comprising: leucine; trileucine; an active agent (IL-13, an antibody), a sugar and a buffer. Gong et al disclose that the excipients including amino acids such as leucine and trileucine may be present from about 1% to about 60 wt% (See [0010], [0048], [0062], [0085], [0090], claim 37 and Table 16).
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The exemplified composition in Table 16 anticipates the claimed formulation as the formulation comprises an antibody, a glass stabilization agent, sucrose, a citrate buffer, leucine and trileucine. Leucine at 64% of the vehicle (assuming at 45% of the composition, 55% being the antibody) and trileucine at 20% of the vehicle amount to 28.8% and 9% respectively and wherein the ratio of leucine to trileucine is 3.2:1, meeting ratio limitation of both claims 1 and 10-11.
Regarding claims 2 and 16, Gong et al teach that the said dry powders preferably have a bulk density ranging from about 0.1-10 g/cc, such as about 0.25-4 g/cc, about 0.5-2 g/cc, or about 0.7-1.4 g/cc (See [0109]).
Regarding claims 6 and 18 Gong et al teach that the composition comprises at least one member selected from dextran, mannitol, raffinose, sorbitol, sucrose, trehalose, etc, (See [0092] and claim 35).
Regarding claim 7, Gong et al teach that the IL-13 antagonist compositions may also include a buffer such as salts of citric acid (to provide the corresponding citrate), ascorbic acid, phosphate buffer (See [0093]).
Regarding claim 33, Gong et al teach that the IL-13 antagonist compositions are delivered to the subject’s lung by inhalation (See [0013], [0044], [0058] and claim 47).
Gong et al do not expressly disclose a composition comprising about 8% to about 11% leucine by weight and about 2% to about 4% trileucine by weight (Claim 1) or about 10.5% leucine and about 2% trileucine by weight (Claim 12).
However, Gong et al disclose that the excipients including amino acids such as leucine and trileucine may be present from about 1 to about 60 wt% (See [0085], [0090], claims 17 and 40).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have followed the teachings of Gong et al to arrive at the instant invention. It would have been obvious to do so because Gong et al teach the claimed compositions comprising dry (micro)particles comprising an active agent and excipients including leucine and trileucine, a buffer and a carbohydrate for administration to a subject’s lung by inhalation and provide guidance on the amount of such excipients. The teachings of Gong et al differ from the examined claims in that Gong et al do not expressly disclose a composition comprising the claimed ranges of leucine and trileucine. However, the broader disclosure clearly points one of ordinary skill in the art to the claimed ranges. That is, while Gong et al’s examples may contain higher amounts of leucine and/or trileucine or not expressly disclose the specific amounts in claims 1 and 12, one of ordinary skill in the art would have been motivated to have selected lower amounts to determine if the lower amounts would provide the same benefits in a dry powder formulation.
Regarding the modifications in concentration ranges, MPEP 2144.05 states “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Thus, the claims would have been obvious because a person of ordinary skill has good reasons 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.
Claims 1-12, 16 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Kuo et al (US 20090117193).
Kuo et al teach a highly dispersible formulation comprising an active agent and a dipeptide or tripeptide comprising at least two leucines, which possesses superior aerosol properties and is thus preferred for aerosolized administration to the lung (See abstract, [0006], [0019] and claim 25).
Regarding claims 1 and 10-12, Kuo et al teach that the said compositions comprise dry powder particles with a mass median diameter of less than about 10 microns (reading on microparticles) and contain from about 1% to about 99% by weight di- or tripeptide, preferably from about 2% to about 75% by weight di- or tripeptide, and even more preferably from about 5% to about 50% by weight di- or tripeptide. A preferred tripeptide is trileucine (See [0009], [0050]-[0051]). The said compositions also comprise an excipient including amino acids such as leucine (See [0019], [0046] and [0055]).
Kuo et al disclose test formulations comprising 5% or 20% leucine or 5% and 20% trileucine and state that tri-leucine is much more effective than leucine in improving the aerosol performance of dry powders. Moreover, a maximum in aerosol performance is typically achieved by the addition of only from about 5%-25% (wt) trileucine (See [0128] and [0133]).
Regarding claims 2 and 16, Kuo et al teach that the dry powder comprises particles having a bulk density from 0.1 to 10 g/cm3 and more preferably from about 0.15-1.5 g/cm3 (see [0009], [0075] and claims 23-24).
Regarding claims 3-8, Kuo et al teach that the said compositions comprise carbohydrate excipients such as fructose, glucose, lactose, sucrose, trehalose, raffinose, dextrans, mannitol, and the like. The compositions may also include a buffer include organic acid salts of citric acid (e.g. sodium citrate), ascorbic acid, acetic acid, phosphate buffers, etc, (See [0057]-[0058] and Table 15).
Regarding claim 9, Kuo et al teach that the active agent may be an antibody (See [0040] and claim 34).
Regarding claim 33, Kuo et al teach that said composition is suitable for delivery to the lung or deep lung by inhalation (See [0014], [0025]-[0026] and claims 2 and 39-40).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have followed the teachings of Kuo et al to arrive at the instant invention. It would have been obvious to do so because Kuo et al teach the claimed compositions comprising dry (micro)particles comprising an active agent and excipients including leucine and trileucine, a buffer and a carbohydrate for administration to a subject’s lung by inhalation and provide guidance on the amount of such excipients. The teachings of Kuo et al differ from the examined claims in that Kuo et al do not expressly disclose a composition comprising the claimed ranges of leucine and trileucine. However, the broader disclosure clearly points one of ordinary skill in the art to the claimed ranges. That is, while Kuo et al’s examples may contain higher amounts of leucine and/or trileucine or not expressly disclose the specific amounts in claims 1 and 12, one of ordinary skill in the art would have been motivated to have selected lower amounts to determine if the lower amounts would provide the same benefits in a dry powder formulation.
Regarding the modifications in concentration ranges, MPEP 2144.05 states “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed.Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Thus, the claims would have been obvious because a person of ordinary skill has good reasons 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.
Response to Arguments
Applicant's arguments filed 05/08/26 have been fully considered but they are not persuasive.
Regarding the teachings of Gong et al, Applicant argues that 1- Gong et al’s disclosure is “nothing more than very general high level generic description of potential compositions, with only paragraph [0090] suggesting numerous alternative excipients which may be selected from in combination with numerous other alternatives. Even assuming all of the suggested alternatives are effective, the cited disclosure amounts to nothing more than an invitation to experiment as it would take an extraordinary amount of trial and tribulation to arrive at Applicant's claimed invention”. 2- “The generic provisions of Gong are in no way sufficient to provide any teaching or suggestion such that one skilled in the art could arrive at the claimed invention. Gong provides no disclosure of any composition comprising each of Isoleucine, Leucine and an active agent, and certainly no composition is provided that one skilled in the art would be led to arrive at a composition within the scope of the claimed parameters” (See remarks, pages 6-7).
The above arguments are not found persuasive. Amendments to claim 1 have removed the rejection of claims under anticipation, however all pending claims are properly rejected as being obvious over Gong et al.
Regarding argument 1, Gong et al teach a dry powder composition comprising IL-13 antagonist, and excipients comprising at least one member selected from carbohydrate, amino acid, peptide, and buffer. It is disclosed that the peptides include trileucine and preferred amino acids include leucine. Furthermore, the said buffer includes leucine. Gong et al teach “One particularly preferred amino acid is the amino acid leucine” (See [0090]). Amino acids including leucine and tri-peptides (such as trileucine) are also considered excellent surface active excipients for the active particles. It is clearly disclosed that suitable excipients can be present in combination. In Tables 16 and 20 trileucine and leucine are combined in a vehicle.
Thus, Gong et al clearly teach a dry powder composition comprising both trileucine and leucine.
Regarding the rejection of claims as being obvious over Kuo et al, Applicant argues that “the disclosure of Kuo neither teaches nor suggests a composition comprising any combination of leucine and trileucine, much less the specific combinations provided by the instant invention. Applicant further submits the teaching of Kuo et al amounts to a teaching away of the instant invention and not only would the results and combination arrived by Applicants not be obvious, but the combination would not be expected to work, much less be necessary nor warranted in view of the findings of Kuo. Kuo does nothing more than compare the characteristics of separate formulations having leucine OR trileucine, concluding trileucine is a far improved reagent over leucine. There is absolutely no suggestion to use leucine in combination with trileucine at any level whatsoever” (See Remarks, page 7).
This argument is also not found convincing. Kuo et al teach a dry powder composition comprising an active agent and a di- or tripeptide comprising at least two leucines. The said tripeptide is preferably trileucine (See claim 13). A method of making the said powder is disclosed and it is then stated that a tri-peptide comprising two leucines and an amino acid selected from the group consisting of leucine (leu), isoleucine (isoleu), etc, is added (See claims 25 and 27). Thus, KUO et al clearly disclose an embodiment wherein trileuicne and leucine are incorporated into the powders comprising the active agent.
Regarding the argument of teaching away, it is noted that 1- while Kuo et al disclose that trileuicne resulted in better performance of the particles, there is a clear teaching of the two compounds being present tether. 2- . In order to teach away, the prior art reference must “criticize, discredit, or otherwise discourage” the claimed invention. In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). This is not the case here. In particular, Kuo et al do not discourage the use of leucine in their powder formulation. They only compare and disclose that trileucine was more effective at lower amounts.
Next argument is that “Only after Applicant's significant investment and evaluation of compositions having a vast array of combinations of excipients was it found the leucine and trileucine content were found to have a significant impact on particle properties. Trileucine was identified as being the primary factor with the largest impact, while leucine was identified as a secondary factor with also a notable impact.
See paragraph [0228]. After significant evaluation of the properties of compositions, it was found the combination of leucine/trileucine allows for reducing the amount needed for leucine or trileucine individually, and to produce a dispersible powder, while increasing the bulk density of the composition. This allows for delivery of a larger dose in a small capsule AND maintains high throughput in the production process which is limited by the amount of leucine or trileucine. In view of the above, neither Gong nor Kuo, provide any suggestion to render the invention as claimed obvious. Neither can support a prima facie case for obviousness of the instant invention, whether alone or in combination” (See Remarks, page 8).
The above argument is similarly found not persuasive. Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978). Looking at the prior art, it is known that leucine is a suitable excipient for powder formulations and that adding trileucine provides added benefits and in small amounts. Gong et al teach that trileucine provides excellent aerosol properties and Kuo et al specifically teaches that presence of trileuince improves the performance of the particles and unexpectedly increased emitted dose of the particles in the aerosol. With this, one with ordinary skill in the art would not see the data presented as unexpected. “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Furthermore, it has been held that “In determining obviousness, neither the particular motivation to make the claimed invention nor the problem the inventor is solving controls. The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” MPEP § 2141.
Claims 1-12, 16 and 33 are rejected. Claims 13, 17, 19, 28 and 30-31 are withdrawn.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
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/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616
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