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
Claim Status
Claims 1-6, 9, 11 and 13-25 are pending. Claim 1 has been amended. Claims 1-6, 9, 11, 13-14 and 24-25 are being examined in this application. In the response to the restriction requirement, Applicants elected Invention I, poloxamer 407, recombinant amelogenin, trehalose (disaccharide), glycine (amino acid) and methionine (antioxidant). Claims 15-23 are withdrawn as being drawn to a nonelected species/invention.
Claim Rejections - 35 USC § 112
The rejection of claims 1-6, 9, 11, 13-14 and 24-25 under 35 USC 112(b) is withdrawn in view of the amendments to the claims.
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.
This rejection is maintained.
Claims 1, 5-6, 9, 11 and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Barthold et al. (WO 2011/051457) in view of Lyngstadaas et al. (WO 2006/064381), Pikal-Cleland et al. (Journal of Pharmaceutical Sciences, Vol. 91, NO. 9, September 2002) and Sturesson et al. (J Control Release. 2000 Jul 3;67(2-3):171-8).
Barthold et al. teach a pharmaceutical, dental and/or cosmetic composition, consisting of a suitable pharmaceutical carrier and purified Enamel Matrix Derivative (EMD) proteins (claim 1), and further teach that EMD comprises amelogenins (page 3, lines 7-10; passim), wherein the amelogenin is recombinant (page 16, lines 14-25).
Barthold et al. also teach that the composition comprises lactose or saccharose (page 26, lines 1-16), and an antioxidant such as ascorbic acid or cysteine (page 24, lines 15-16).
Barthold et al. further teach that “[a]n EMD protein according to the present invention can be incorporated into a polymeric matrix so that it is released by degradation of the polymeric matrix, by enzymatic action and/or by diffusion. Said polymeric matrix is either suitable for cellular in-growth, or cell-occlusive. Comprised in the invention is thus in particular a pharmaceutical, dental and/or cosmetic composition according to the present invention at a low total concentration within the formulation, wherein a spatial and/or selective regulation of release of said active enamel substance permits a great percentage of the active enamel substance to be released at the time of appropriate cellular activity. Polymeric matrices suitable for the purpose of the present invention are e.g. disclosed in WO 2006/064381” (page 25, lines 1-11; page 31, lines 5, 22 and 29).
Barthold et al. additionally teach that the EMD is lyophilized (page 29, lines 1-11).
Barthold et al. do not specifically teach that the disaccharide is trehalose; and that the composition comprises a poloxamer copolymer; and an amino acid selected from Ala, Gly, Ile, Leu, Pro, Val, and mixtures thereof.
Lyngstadaas et al. teach poly(ethylene oxide)-co-d(propylene oxide) block copolymers (i.e. a poloxamer copolymer) (para bridging pages 14-15).
Pikal-Cleland et al. teach that “[P]roteins are exposed to several stresses during freeze–thawing and the freezing step of lyophilization, as well as during storage of the frozen protein solution”, and further teach that “[P]revious studies have shown that glycine is one of many solutes that stabilize proteins via the preferential exclusion mechanism. Although this theory was originally defined for nonfrozen aqueous solutions, experimental evidence has demonstrated its validity for frozen systems as well” (page 1970, left column, 2nd para).
Sturesson et al. teach that “[I]n order to retain a high degree of bioactivity, the well-known protein stabilizers: sucrose, trehalose and poloxamer 407, were added to the urease in the preparation. The bioactivity of the entrapped urease was reduced more by methylene chloride than by ethyl acetate. The gelled form of poloxamer was shown to highly favor the retention of bioactivity, demonstrated by an increase of 41% compared to preparations without poloxamer. Moreover, the presence of poloxamer strongly increased the in vitro release rate of urease from the microspheres. The entrapment efficiency was increased by 44% using the sugars in the preparation. These results clearly show the great potential of small quantities of additive in the formulation to control the properties of the microspheres. The amount and type of additive could be adjusted according to the therapeutic application of the preparation” (abstract).
It would have been obvious to one of ordinary skill in the art to use the poloxamer copolymer of Lyngstadaas et al. in the invention of Barthold et al., because Barthold et al. teach that polymeric matrices suitable for the purpose of the present invention are disclosed in WO 2006/064381 (i.e. Lyngstadaas et al.).
The skilled artisan would have been motivated, with a reasonable expectation of success, to add glycine to the resulting composition because Pikal-Cleland et al. teach that glycine stabilizes proteins during freeze–thawing and the freezing step of lyophilization, as well as during storage of the frozen protein solution.
Furthermore, the MPEP 2144.06 states that it is obvious to substitute equivalents known for the same purpose.
Therefore, it would have been obvious to one of ordinary skill in the art to substitute the disaccharide of Barthold et al. with the disaccharide of Sturesson et al.
With respect to the claimed concentration of the various components, the MPEP 2144.05 A states that “[G]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see 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)”.
Since Applicant has not disclosed that the specific limitations recited in the instant claims are for any particular purpose or solve any stated problem, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum concentration of the various components, pH and viscosity by normal optimization procedures known in the pharmaceutical art.
With respect to claims 24-25, Barthold et al. teach that “[A] pharmaceutical, dental and/or cosmetic composition according to the present invention to be administered, may be adapted for administration by any suitable route, e.g. by systemic administration to a patient through a hose, syringe, spray or draining device (page 20, lines 28-30). Therefore, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to make a kit comprising the composition in a delivery mean such as a syringe.
This rejection is maintained.
Claims 1-6, 9, 11, 13-14 and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Barthold et al. (WO 2011/051457) in view of Lyngstadaas et al. (WO 2006/064381), Pikal-Cleland et al. (Journal of Pharmaceutical Sciences, Vol. 91, NO. 9, September 2002) and Sturesson et al. (J Control Release. 2000 Jul 3;67(2-3):171-8) as applied to claims 1, 5-6, 9, 11 and 24-25 above, and further in view of Bodratti et al. (J Funct Biomater. 2018 Jan 18;9(1):11).
The teachings of Barthold et al., Lyngstadaas et al., Pikal-Cleland et al. and Sturesson et al. with respect to claims 1, 5-6, 9, 11 and 24-25 have been discussed above.
Barthold et al., Lyngstadaas et al., Pikal-Cleland et al. and Sturesson et al. do not teach the poloxamer is poloxamer 407.
Bodratti et al. teach that “[P]oloxamer 407 is widely used because it can form hydrogels at lower block copolymer concentrations in water” (page 5, 2nd para).
The MPEP 2144.06 states that it is obvious to substitute equivalents known for the same purpose.
In the instant case, it would have been obvious to one of ordinary skill in the art to substitute the poloxamer of Lyngstadaas et al. for the poloxamer of Bodratti et al.
With respect to claims 4 and 13-14, the MPEP 2144.05 A states that “[G]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); 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) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see 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)”.
Since Applicant has not disclosed that the specific limitations recited in the instant claims are for any particular purpose or solve any stated problem, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum concentration of the poloxamer 407, the disaccharide, the amino acid, and the antioxidant, by normal optimization procedures known in the pharmaceutical art.
Response to Arguments
Applicant’s arguments filed on 7/24/2026 have been fully considered but they are not persuasive.
Applicant argues that “[C]laim 1 expressly requires a "thermosensitive liquid medical composition." The claimed composition must remain a liquid having a viscosity of up to 2,000 mPa- sec at approximately 2- 8°C. Thus, Claim 1 is directed to a composition formulated, stored, and handled as a refrigerated liquid before administration - not to a frozen or lyophilized composition”.
Applicant also argues that “[B]arthold discloses a liquid pharmaceutical composition, as does the claimed invention, which expressly requires that the medical composition be a thermosensitive "liquid" at approximately 2-8°C. Neither Barthold's liquid composition nor the claimed liquid composition is subjected to the freezing or lyophilization conditions disclosed in Pikal-Cleland. Consequently, the particular problem for which glycine is used in Pikal-Cleland - protection against freezing- induced protein damage - does not arise in Barthold's liquid composition. Therefore, Applicant respectfully submits that a person having ordinary skill in the art would not have any basis or motivation to add glycine into the liquid medical composition disclosed in Barthold to arrive the claimed liquid medical composition”.
Applicant further argues that “[T]he present specification as filed discloses at Paragraph [0008] that "there is a need for stable and biologically potent amelogenin-based products. Such products should be sterile, stable, reproducible in large quantities, and easily injectable. Thus, the unexpected nature of the result must be measured against the ability to produce such a stable product. Applicant has discovered that the addition of the precise components now recited in the claim, namely trehalose, glycine, and methionine, can produce such a stable product. As shown in Table 5, compositions containing all three of these components produce a stabilized thermosensitive product of amelogenein and poloxamer, while compositions that lack these components were unable to do so”.
Applicant’s arguments are not persuasive.
Barthold et al. clearly teach that “[A] composition for use in accordance with the present invention may be, but is not limited to, in the form of,… freeze-dried powders” (page 21, lines 16-28).
On the other hand, Pikal-Cleland et al. teach that glycine stabilizes proteins during freeze–thawing and the freezing step of lyophilization, as well as during storage of the frozen protein solution.
Therefore, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to add glycine to the composition obvious over the cited references.
The skilled artisan would have expected the addition of glycine to stabilize the claimed recombinant amelogenin during the freezing step of lyophilization, as well as during storage because Pikal-Cleland et al. teach that glycine stabilizes proteins during freeze–thawing and the freezing step of lyophilization, as well as during storage of the frozen protein solution.
With respect to Applicant’s arguments regarding unexpected results, from the teachings of Barthold et al., Lyngstadaas et al., Pikal-Cleland et al. and Sturesson et al., it is clear that one of ordinary skill in the art would have expected glycine to stabilize amelogenin during freeze–thawing, the freezing step of lyophilization, and during storage of frozen amelogenin solution.
For these reasons, the rejections are maintained.
Conclusion
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.
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/SERGIO COFFA Ph.D./
Primary Examiner
Art Unit 1658
/SERGIO COFFA/Primary Examiner, Art Unit 1658
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