DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 31, 2026, has been entered.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in India on August 16, 2019. It is noted, however, that applicant has not filed a certified copy of the IN 201941033024 application as required by 37 CFR 1.55.
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.
Claims 1 and 3-4 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The claims are drawn to a method of preparation of a hydrogel comprising a plurality of pharmaceutically active protein crystals comprising a seed-mediated crystallization technique. BRI of the genus “pharmaceutically active protein crystals” includes crystalline forms of all proteins that have therapeutic utility. These proteins vary in size, amino acid sequence, physical properties, solubility, and function.
The original specification discloses one embodiment of the invention: hydrogels containing insulin crystals (Examples 1 and 2). As discussed above the claim scope is very broad; in comparison, the scope of the description which only includes a single species of pharmaceutically active protein crystal, is extremely narrow. The actual reduction to practice does not include species characterized by other sequences, folds, sizes, or functions. One of ordinary skill in the art would not consider insulin to be representative of the full scope of the claimed genus of pharmaceutically active protein crystals. Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
The specification provides guidance for seed-mediated crystallization that is specific for insulin. The specification describes appropriate precipitate solutions, hydrogel composition, seed-syrup formation, and hydrogel formation for insulin alone (Examples 1 and 2). The specification characterizes the size of the crystals formed for insulin in the hydrogel formulations (Figure 4).
The specification does not describe a general correlation between the details of the seed-mediated crystallization technique including appropriate precipitate solutions and conditions, hydrogel composition, seed-syrup formation, and hydrogel formation for the entire claimed genus of pharmaceutically active proteins. Protein crystallization conditions are unpredictable and must be empirically determined. As a result, it is impossible to predict, based on the specification, how changing the protein will affect the details of the method, or even if a protein crystal can be formed.
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention. In conclusion, only insulin, satisfies the written description requirements of 35 U.S.C. 112(a).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In claim 1, the indefinite language is “homogenous”. The language is indefinite because it is unclear which parameter pertaining to the seeds-syrup is homogenous. For example, the seeds-syrup could have a homogenous crystal size. Alternatively, the seeds-syrup could have a homogenous protein composition. Because the term is unclear, the metes and bounds of the claim are indefinite.
In claim 1, the indefinite language is step c. The language is indefinite because the effect of the step is unclear. The step explicitly requires that the mixed solution is allowed to gel but is silent with respect to crystallization and/or crystal growth. Therefore, it is not clear whether or not the step of adding the seeds-syrup to the supersaturate solution of protein results in any crystallization and/or crystal growth. It is also unclear whether the supersaturate solution of pharmaceutically active protein system is a “final crystallization medium” as recited in step b.
Dependent claims 2-4 fail to remedy these issues and are likewise rejected.
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.
Claims 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over WO/2017/191323.
This is a new rejection necessitated by the amendment filed January 29, 2026.
WO/2017/191323 teaches a composition comprising a hydrogel and pharmaceutically active protein crystals grown in-situ within the hydrogel, wherein the average size of the crystal is less than 20 microns (see page 2, line 6 - page 3, line 4; page 6, lines 8-20; page 7, line 32 -page 8, line 19). The protein active solution is preferably a solution comprising insulin (Examples 1-5).
In one embodiment, WO/2017/191323 reduces to practice an agarose hydrogel formulation comprising insulin crystals (Example 1). The concentration of insulin is 8 mg/ml in 6 mM HCl, 5 mM ZnCl2, 16 mM sodium citrate, pH 7.0, 15% DMSO, and 0.04% agarose. The average size of the insulin crystal is 75% with a size of 8.5 + 1.15 micron and 25% with average size of 5.56 + 0.87 microns, which qualifies as a microcrystal.
In one embodiment, WO/2017/191323 teaches a di-alanine hydrogel formulation comprising insulin crystals (Example 2). The concentration of insulin is 5 mg/ml in 6 mM HCl, 5 mM ZnCl2, 22 mM sodium citrate, pH 7.0, and 0.2% di-alanine. The average size of the insulin crystal is 90.6% with a size of 10.28 + 2.13 micron and 9.4% with average size of 5.78 + 2.13 microns, which qualifies as a microcrystal.
A comparison between claim 5 as amended and the prior art is as follows:
Claim 5
WO/2017/191323
A formulation of hydrogel
In Example 1, the formulation is an agarose hydrogel.
In Example 2, the formulation is a di-alanine hydrogel.
WO/2017/191323 also teaches that the hydrogel comprises agarose, gelatin, carrageenan, or poly(ethylene glycol) (PEG) (p. 9, lines 20-22; claim 2).
Therefore, the reference satisfies the limitation “a formulation of hydrogel”.
the formulation comprises a pharmaceutically active protein crystal
In both Examples 1 and 2, the hydrogel comprises a pharmaceutically active protein crystal, insulin crystals.
Therefore, the reference satisfies the limitation “the formulation comprises a pharmaceutically active protein crystal”.
at a concentration of 10 mg/ml to 15 mg/ml
In Examples 1 and 2, the insulin concentration is 8 mg/ml and 5 mg/ml, respectively.
Therefore, the reference does not explicitly teach the limitation “at a concentration of 10 mg/ml to 15 mg/ml”.
wherein active protein microcrystal is insulin.
In Example 1, the average size of the insulin crystal is 75% with a size of 8.5 + 1.15 micron and 25% with average size of 5.56 + 0.87 microns, which qualifies as a microcrystal.
In Example 2, the average size of the insulin crystal is 90.6% with a size of 10.28 + 2.13 micron and 9.4% with average size of 5.78 + 2.13 microns, which qualifies as a microcrystal.
Therefore, the reference satisfies the limitation “wherein active protein microcrystal is insulin”.
The difference between the reference and claim 5 is the concentration of active protein crystal. The reference teaches 8 mg/ml and 5 mg/ml, which is close to but outside of the claimed range of 10 mg/ml to 15 mg/ml.
MPEP § 2144.05(I) states: a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).
In the instant case, the claimed range of insulin crystal concentration of 10 mg/ml to 15 mg/ml is close to the prior art disclosure of 5 mg/ml (Example 2) and 8 mg/ml (Example 1). There is no evidence on record that the claimed range is critical compared to the claimed range. In fact, both the instant application and prior art indicate that the formulations are suitable for therapeutic use. Therefore, the claimed range is prima facie obvious over the prior art.
MPEP § 2144.05(II)(A) states: Generally, 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)
In the instant case, it would have been routine optimization to arrive at the claimed invention because the claimed parameter insulin concentration is recognized as a result-effective variable, i.e., a variable which achieves a recognized result. Insulin is recognized as a therapeutically active protein and the formulation is intended for pharmaceutical use (page 10, lines 23-35). Therefore, insulin concentration (i.e. dose) is result-effective.
For these reasons, the formulation of claim 5 is prima facie obvious over the prior art.
With respect to claims 6 and 10, WO/2017/191323 teaches that the hydrogel is macromolecular and comprises or consists of a compound selected from the group consisting of gelatin, carrageenan, or Poly(ethylene glycol) (PEG) (p. 9, lines 20-22; claim 2). Preferably, the PEG hydrogel is composed of poly(ethylene glycol) monomethyl ether monomethacrylate (PEGMA) of average molecular weight (MW) 1 100 Da cross-linked with poly(ethylene glycol) dimethacrylate (PEGDMA) of MW 1200 Da (p. 9, lines 24-27; claim 8).
With respect to claims 7-8, WO/2017/191323 teaches that the hydrogel is the di-alanine hydrogel comprises Fmoc-AA-OH, which is the dipeptide N-(9-fluorenylmethoxycarbonyl)-L-alanine-L-alanine (p. 10, lines 7-8; claim 7).
With respect to claim 9, WO/2017/191323 teaches that the agarose gel comprises or consists of polysaccharides of agarobiose units, wherein agarobiose is a disaccharide formed by the union of D-galactose and 3,6-anhydro-L-galactose (p. 9, lines 22-24; claim 6).
The limitation “prepared by a seeding technique resulting in a narrow size distribution and a homogenous suspension” is a product by process limitation. Determination of patentability is based on the product itself (MPEP § 2113). There is no evidence on record that the claimed hydrogel containing insulin crystals is structurally distinct from the prior art. The reference states that for therapeutic treatment a narrow range of crystal sizes with an average size of 20 or less microns is needed (p. 1, lines 32-34). Burden is shifted to Applicant to provide evidence in the form of a comparison between the claimed invention and prior art.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over WO/2017/191323 in view of U.S. Patent No. 2,799,622, U.S. Patent No. 6,566,490, Bergfors (Succeeding With Seeding: Some Practical Advice in R.J. Read and J.L. Sussman (eds.): Evolving Methods for Macromolecular Crystallography, 1–10, 2007, Springer; hereafter “Bergfors 2007”), and Bergfors (Seeds to crystals. Journal of Structural Biology 142 (2003) 66-76; hereafter “Bergfors 2003”).
The previous rejection is modified to include the teachings of Bergfors 2007 and Bergfors 2003 in order to better address the claim amendments filed January 29, 2026.
WO/2017/191323 teaches (see page 2, line 6 - page 3, line 4; page 6, lines 8-20; page 7, line 32 -page 8, line 19) a process to manufacture a composition comprising a hydrogel comprising a plurality of pharmaceutically active protein crystals grown in-situ within the hydrogel, wherein the pharmaceutically active protein crystals grown in-situ have an average size of 20 or less microns which comprises:
a. Sequentially blending a pharmaceutically active protein solution in an appropriate buffer composition by using a value of supersaturation in the metastable zone width (MSZW) or nearby the supersolubility curve, with a precipitant solution, wherein acetone is absent, and a gelator solution,
b. Inducing the nucleation by lowering the temperature, and
c. Storing the resulting mix at a constant temperature, preferably at room temperature at 1 atm (page 8, lines 4-19).
The protein active solution is preferably a solution comprising insulin (Examples 1-5).
The precipitant solution is preferably HCI, ZnCl2 and sodium citrate (Example 1).
The gelator solution is preferably the Fmoc-AA-OH hydrogel (Example 1).
In one embodiment, WO/2017/191323 teaches an agarose hydrogel formulation comprising insulin crystals (Example 1). The concentration of insulin is 8 mg/ml in 6 mM HCl, 5 mM ZnCl2, 16 mM sodium citrate, pH 7.0, 15% DMSO, and 0.04% agarose. The average size of the insulin crystal is 75% with a size of 8.5 + 1.15 micron and 25% with average size of 5.56 + 0.87 microns.
In one embodiment, WO/2017/191323 teaches a di-alanine hydrogel formulation comprising insulin crystals (Example 2). The concentration of insulin is 5 mg/ml in 6 mM HCl, 5 mM ZnCl2, 22 mM sodium citrate, pH 7.0, and 0.2% di-alanine. The average size of the insulin crystal is 90.6% with a size of 10.28 + 2.13 micron and 9.4% with average size of 5.78 + 2.13 microns.
The protein crystals grown in situ in WO/2017/191323 can be used directly in therapy (page 10, lines 23-35).
With respect to claim 1, WO/2017/191323 teaches a method of preparing a hydrogel formulation comprising pharmaceutically active protein crystals comprising crystalizing the protein in the presence of a hydrogel precursor in step c) and step d). The reference does not teach the steps of obtaining a crystal through ex-situ nucleation, in step a), crushing the crystal to make a homogenous seed syrup in step b), or mixing the seed syrup with the supersaturate solution and gelator in step c). Instead, the reference teaches inducing crystallization through spontaneous nucleation by lowering the temperature.
This difference is obvious in view of the prior art which contains numerous examples of using the seed-mediated technique for insulin crystallization.
Bergfors 2007 and Bergfors 2003 review the technique of seed-mediated crystallization. Bergfors 2003 teach that seeding separates nucleation and growth phases of crystallization by introducing previously nucleated crystals as seeds into new supersaturated solutions (p. 66, col 1). Bergfors 2007 states that the seeding technique is “powerful” and “cheap, fast and easy” and can be used to “improve crystal quality” (section 1).
U.S. Patent No. 2,799,622 discloses the use of seed-mediated crystallization for the crystallization of insulin. The use of the seed-mediated technique yields a composition containing insulin crystals that are substantially uniform in size (col 2, lines 20-25; Example 1). U.S. Patent No. 2,799,622 teaches that the size distribution is determined by the quantity of seed crystals employed, the size of the seed crystals, and the insulin concentration during crystallization (col 2, lines 26-32). U.S. Patent No. 2,799,622 teaches that production of insulin crystals that are uniform in size is achieved by preventing spontaneous crystallization and instead using seed crystals (col 2, lines 68-71). See Examples 1-7 which reduce to practice methods of producing seed crystals and adding a homogenous suspension of seed crystals to an insulin solution to yield insulin crystals of predetermined size and narrow size distribution.
U.S. Patent No. 6,566,490 also discloses the use of seed-mediated crystallization for the crystallization of insulin. As with U.S. Patent No. 2,799,622, U.S. Patent No. 6,566,490 teaches that the use of the seed-mediated technique yields a composition containing insulin crystals that are substantially uniform in size and that have a narrow particle size distribution (col 2, lines 20-26; claim 1).
It would have been obvious to substitute the seed-mediated crystallization technique of U.S. Patent No. 2,799,622, U.S. Patent No. 6,566,490, Bergfors 2007, and/or Bergfors 2003 for the spontaneous nucleation temperature-mediated crystallization technique in the method of making a hydrogel containing insulin crystals taught by WO/2017/191323. The resulting method would have the advantages of the hydrogel carrier disclosed by WO/2017/191323 such as increased stability, and a slow-release profile (Examples 5 and 6). In addition, the resulting method would have the advantage of having crystals with a uniform size distribution, as taught by U.S. Patent No. 2,799,622 (col 2, lines 20-32; Example 1) and U.S. Patent No. 6,566,490 (col 2, lines 20-26; claim 1). The resulting method would use a seed-mediated crystallization technique to prepare a hydrogel formulation comprising protein crystals, comprising all of steps a)-d) of claim 1
(a) blending a pharmaceutically active protein solution in a precipitate solution (101) to induce ex-situ nucleation and obtain one or more protein crystals;
Bergfors 2003 and Bergfors 2007 teach that the technique of seed-mediated crystallization comprises an initial step obtaining a crystal that is subsequently used to seed a new supersaturated solution in the metastable zone (Bergfors 2003 p. 66, col 1, Sections 2.1-2.2, Figure 3; Bergfors 2007, Sections 3.1-4, Figure 2(a)).
U.S. Patent No. 2,799,622 teaches that insulin crystalizes in the presence of a crystallization-promoting metal, preferably zinc (col 2, lines 27-48). BRI of the claimed precipitate solution includes the solution containing the crystallization-promoting metal in the prior art. This step would occur outside of the hydrogel formulation.
WO/2017/191323 teaches that insulin crystalizes in the presence of a precipitant solution comprising HCI, ZnCI2 and sodium citrate (p. 8, lines 26-28).
It would have been obvious to use a supersaturated solution in the presence of a precipitant known to promote crystallization of insulin to make the seed syrup ex-situ that is needed for the seed-mediated technique of Bergfors 2003, Bergfors 2007, U.S. Patent No. 2,799,622, and U.S. Patent No. 6,566,490.
(b) crushing the obtained protein crystals outside a final crystallization medium to produce a homogenous seeds-syrup (102);
After obtaining one or more protein crystals, it would have been obvious to crush the crystals to produce a homogenous seeds-syrup.
U.S. Patent No. 6,566,490 teaches a method for producing seeding microcrystals for the production of a peptide or protein, comprising providing an unseeded suspension of a peptide or protein and homogenizing said suspension under pressure to result in peptide or protein microcrystals suitable for use as seeding microcrystals (col 2, lines 27-33). BRI of the claim term crushing includes the homogenization under pressure step in the prior art. The step of making the seed syrup occurs outside of the final crystallization medium.
Bergfors 2007 states on page 3: “to make a seed stock, the parent crystals are transferred in some of their mother liquor to a microcentrifuge tube. Glass tissue homogenizers, Seed Beads (Hampton Research, Inc.), sonication, vortexing, acupuncture needles, dentist’s tools, etc. can be used to crush the crystals into a crystal slurry; the actual method of generating the seeds is not critical. What is important is that the seeds are collected and stored in a mother liquor where they are stable, i.e., do not dissolve or become contaminated by microbial growth.” BRI of the claim term crushing includes the use of glass tissue homogenizers, Seed Beads (Hampton Research, Inc.), sonication, vortexing, acupuncture needles, dentist’s tools, etc. to crush a crystal into a slurry as taught by Bergfors 2007. It is clear from Bergfors 2007 that this step occurs outside of the final crystallization medium
(c) mixing 1% v/v of the homogeneous seed-syrup with a supersaturate solution of the pharmaceutically active protein solution containing the hydrogel precursor and allowing a mixed solution to gel (103);
After obtaining one or more protein crystals, and crushing the crystals to produce a homogenous seeds-syrup, it would have been obvious to mix the seed-syrup with a supersaturated solution of the protein and hydrogel precursor and to allow the mixed solution to gel.
WO/2017/191323 teaches sequentially blending a pharmaceutically active protein solution in an appropriate buffer composition by using a value of supersaturation in the metastable zone width (MSZW) or nearby the supersolubility curve, with a precipitant solution, wherein acetone is absent, and a gelator solution, and then initiating crystallization (page 8, lines 4-19).
U.S. Patent No. 2,799,622 teaches adding homogenous seed-syrup to a solution of the pharmaceutically active protein (Examples).
Therefore, instead of inducing the nucleation spontaneously by lowering the temperature as in WO/2017/191323 step b), one of ordinary skill in the art would add homogenous seed-syrup to a solution of the pharmaceutically active protein as in U.S. Patent No. 2,799,622 to the pharmaceutically active protein solution in an appropriate buffer composition by using a value of supersaturation in the metastable zone width (MSZW) or nearby the supersolubility curve, with a precipitant solution, wherein acetone is absent, and a gelator solution, to induce crystallization. See also U.S. Patent No. 6,566,490.
The seed-mediated crystallization technique is further explained by Bergfors 2007 by showing a theoretical phase diagram (Figure 2(a)):
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Bergfors 2007 states (page 7): “The thick black line represents the limit of solubility. Below this line, the solution is undersaturated and above it, supersaturated. Seeds placed in an undersaturated solution dissolve. Spontaneous nucleation occurs in the labile zone of the supersaturated phase, but the best crystal growth occurs in the metastable region. At the highest levels of supersaturation, the solid phase aggregates in a disordered fashion, seen as precipitate.” It is clear from this description that the seed-mediated technique requires transferring the seed crystal syrup to the final crystallization solution, which in the case of WO/2017/191323 includes a hydrogel precursor.
Regarding the “1% v/v” limitation, it would have been obvious to optimize the amount of the homogenous seed-syrup given that this amount is a result-effective variable (MPEP § 2144.01(II)). U.S. Patent No. 2,799,622 teaches that the size distribution is determined by the quantity of seed crystals employed, the size of the seed crystals, and the insulin concentration during crystallization (col 2, lines 26-32). Bergfors 2003 teaches that after crushing, a dilution series of the seed stock in a stabilizing mother liquor can be prepared and used to experimentally determine the solution with the optimal number of nuclei (i.e. seeds) (p. 67, col 1). It would have been obvious to optimize the quantity of seed crystals employed, which is a function of the volume of homogenous seed-syrup added, in order to achieve the desired insulin crystal size distribution.
Finally, WO/2017/191323 also teaches that gelation occurs to yield a hydrogel containing a plurality of insulin crystals (see Examples which show a hydrogel containing insulin crystals).
(d) storing the resulting hydrogel mixture at room temperature and at an atmospheric pressure at 101325 Pa i.e. at 1 atmospheric pressure (104).
WO/2017/191323 teaches storing the resulting mix at a constant temperature, preferably at room temperature at 1 atm (page 8, lines 4-19).
One of ordinary skill in the art would have been motivated to make the aforementioned substitution given that WO/2017/191323, U.S. Patent No. 2,799,622, and U.S. Patent No. 6,566,490 are directed to making insulin crystals with uniform, narrow size distributions that are compatible with pharmaceutical use and that U.S. Patent No. 2,799,622, and U.S. Patent No. 6,566,490 teach that seed-mediated crystallization technique yields insulin crystals with uniform, narrow size distributions. There would have been a reasonable expectation of success given that crystal seeding is well-established in the prior art, as evidenced by the fact that U.S. Patent No. 2,799,622 was published in 1957, and the reviews published by Bergfors 2003 and Bergfors 2007.
With respect to claim 2, Examples 1 and 2 of WO/2017/191323 include insulin.
With respect to claim 3, WO/2017/191323 teaches that the precipitant solution is HCI, ZnCI2 and sodium citrate, and that preferably, the concentration of HCI is between 5 and 20 mM, the concentration of ZnCI2 is approx. 5 mM and the concentration of sodium citrate is between 15 and 50 mM (p. 8, lines 26-28). It would have been obvious to use a solution known to promote crystallization of insulin to induce ex-situ nucleation of the insulin prior to crushing to make the seed syrup according to the methods of Bergfors 2003, Bergfors 2007, U.S. Patent No. 2,799,622, and U.S. Patent No. 6,566,490.
With respect to claim 4, WO/2017/191323 teaches (see page 2, line 6 - page 3, line 4; page 6, lines 8-20; page 7, line 32 -page 8, line 19) a process to manufacture a composition comprising a hydrogel comprising pharmaceutically active protein crystals grown in-situ within the hydrogel, wherein the pharmaceutically active protein crystals grown in-situ have an average size of 20 or less microns.
U.S. Patent No. 2,799,622 teaches that the use of the seed-mediated technique yields a composition containing insulin crystals that are substantially uniform in size (col 2, lines 20-25; Example 1). U.S. Patent No. 2,799,622 teaches that the size distribution is determined by the quantity of seed crystals employed, the size of the seed crystals, and the insulin concentration during crystallization (col 2, lines 26-32). U.S. Patent No. 2,799,622 teaches that production of insulin crystals that are uniform in size is achieved by preventing spontaneous crystallization and instead using seed crystals (col 2, lines 68-71). See Examples 1-7 which reduce to practice methods of producing seed crystals and adding a homogenous suspension of seed crystals to an insulin solution to yield insulin crystals of predetermined size and narrow size distribution.
U.S. Patent No. 6,566,490 also teaches that the use of the seed-mediated technique yields a composition containing insulin crystals that are substantially uniform in size and that have a narrow particle size distribution (col 2, lines 20-26; claim 1).
With respect to claims 5-10, the method above would yield a hydrogel formulation with active insulin protein crystals. The protein crystals grown in situ in WO/2017/191323 can be used directly in therapy as pharmaceutical formulations (page 10, lines 23-35).
Regarding claim 5, it would have been obvious to optimize the concentration through routine optimization given that this amount is a result-effective variable (MPEP § 2144.01(II)). U.S. Patent No. 2,799,622 teaches that the size distribution is determined by the quantity of seed crystals employed, the size of the seed crystals, and the insulin concentration during crystallization (col 2, lines 26-32). It would have been obvious to optimize the insulin concentration in order to achieve the desired crystal size distribution. It would have been further obvious to optimize insulin concentration in order to achieve a therapeutically-effective dose.
With respect to claims 6 and 10, WO/2017/191323 teaches that the hydrogel is macromolecular and comprises or consists of a compound selected from the group consisting of agarose, gelatin, carrageenan, Poly(ethylene glycol) (PEG) (p. 9, lines 20-22; claim 2). Preferably, the PEG hydrogel is composed of poly(ethylene glycol) monomethyl ether monomethacrylate (PEGMA) of average molecular weight (MW) 1 100 Da cross-linked with poly(ethylene glycol) dimethacrylate (PEGDMA) of MW 1200 Da (p. 9, lines 24-27; claim 8).
With respect to claims 7-8, the di-alanine hydrogel comprises Fmoc-AA-OH, which is the dipeptide N-(9-fluorenylmethoxycarbonyl)-L-alanine-L-alanine (p. 10, lines 7-8; claim 7).
With respect to claim 9, WO/2017/191323 teaches that the agarose gel comprises or consists of polysaccharides of agarobiose units, wherein agarobiose is a disaccharide formed by the union of D-galactose and 3,6-anhydro-L-galactose (p. 9, lines 22-24; claim 6).
Response to Arguments
Applicant's arguments filed January 29, 2026, have been fully considered but they are not persuasive.
Pages 4-8 present arguments against individual references WO/2017/191323, U.S. Patent No. 2,799,622, and U.S. Patent No. 6,566,490. These arguments are repeated on pages 9-10 for claims 1-2, and on page 11 for claim 3. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In addition, the rejection has been modified to address the amended claim limitations, in part through the citation of new references.
On page 11, Applicant asserts unexpected technical effects of the invention including:
Formation of insulin microcrystals with uniform and controlled size distribution;
Stability at room temperature and atmospheric pressure; and
Predictable and controlled release of insulin from the hydrogel matrix.
These effects are also asserted on page 12 for claim 3. On page 13, regrading claim 4, Applicant further asserts that the process yields a narrow size distribution, which in turn yields a more predictable and controlled release profile, attributable to uniform surface area and dissolution kinetics.
To establish unexpected results, applicant must provide an affidavit or declaration under 37 CFR 1.132 that compares the claimed subject matter with the closest prior art (MPEP § 716.02(e)). In the instant case, Applicant must present a comparison between the claimed invention and the formulations of WO/2017/191323 with respect to size distribution of the insulin microcrystals in the hydrogel, stability at room temperature and atmospheric pressure, and controlled release of insulin from the hydrogel matrix. In addition, evidence of unexpected results must be commensurate in scope with the claims (MPEP § 716.02(d)). Finally, the evidence relied upon should establish that the differences are unexpected and have both statistical and practical significance (MPEP § 716.02(b)). Because Applicant has failed to provide a comparison, the prima facie case is maintained for claims 1-4.
On page 14, regarding claims 5-10, Applicant argues that the rejection does not address the criticality of the claimed size range. However, the claims have been amended to remove the size range limitation. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., crystal size, narrow size distribution) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
On pages 15-17, regarding claims 6-9, Applicant argues that WO/2017/191323 fails to teach formulating pre-formed insulin microcrystals, encapsulating insulin microcrystals having a defined average size and concentration, and using the hydrogel as a post-crystallization stabilizing and delivery matrix. Applicant argues that WO/2017/191323 is directed to the process of growing crystals in hydrogels, whereas the claimed invention emphasizes formulating pre-formed microcrystals into hydrogels. These arguments are not persuasive because they again rely on features that are not recited by the claims. In addition, the arguments on pages 15-19, regarding claims 6-9, are piecemeal arguments against individual references. The rejections are based on combinations of references. Finally, Applicant has failed to show, by way of a comparison between the claimed invention and the closest prior art, that the claimed invention has unexpected properties.
For these reasons, the rejection is maintained.
Conclusion
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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