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
Claims 1, 5-11, 13-14, 16, and 23-24 are pending and under examination on their merits. Claims 2-4, 15, 17-22, and 25 were cancelled previously. Claim 12 is newly cancelled.
Response to Arguments
Applicant's arguments filed 6/22/2026 have been fully considered but they are not persuasive.
Specifically, Applicant argues that the amendment overcomes the written description rejection under 35 U.S.C. 112(a) (Arguments, paragraph 1 on page 6). However, the amendment only partially addresses the written description rejection of the claims under 35 U.S.C. 112(a). The broadest reasonable interpretation of claim 1 encompasses liquid compositions comprising the porous major ampullate spidroin protein in the form of particles. However, the particles with the claimed surface area are lyophilized (see Example 5 of the specification, [0292] on page 54). Furthermore, claim 13 recites mixing a MaSp with a liquid comprising an organic solvent to obtain a
mixture; and removing said liquid from said mixture by lyophilization. However, Applicant’s disclosure is limited to liquids consisting of tert-butanol, water or tert-butanol and water ([292]). In other words, the person of ordinary skill in the art would not have recognized that Applicant was in possession of the claimed genus of method conditions, which includes mixing the MaSp with liquids comprising other organic solvents in addition to tert-butanol. Lyophilization only results in MaSp particles with a BET surface area of about 180 m2/g when the MaSp particles are mixed with pure tert-butanol (specification [0305]). Therefore, the claims are still rejected under 35 U.S.C. 112(a) (written description).
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.
(New Rejection Necessitated by Amendment) Claims 1, 5-11, 13-14, 16, and 23-24 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.
Claim 1 is drawn to a composition comprising a porous major ampullate spidroin protein (MaSp), wherein the MaSp is characterized by a BET surface area of about 180 m2/g and a residual amount of tert-butanol below 100 ppm, wherein the MaSp is in the form of particles having an average size in the range between 0.5 microns and 2 microns. The broadest reasonable interpretation of claim 1 includes liquid compositions as well as dried or lyophilized compositions because the claim preamble does not limit the state of the composition of matter.
Claim 13 is drawn to a method for obtaining a dried major ampullate spidroin protein (MaSp), comprising mixing a MaSp with a liquid containing t-butanol to obtain a mixture, and removing the liquid from the mixture by lyophilization, thereby obtaining a dried MaSp characterized by a BET surface area of about 180 m2/g and a residual amount of t-butanol below 100 ppm. The “liquid comprising an organic solvent” is not limited to aqueous solutions with t-butnaol as the only organic solvent (“comprising” is interpreted as open).
The specification discloses the recombinant production of major ampullate spidroin (MaSp)-based fiber using bacteria ([0291]). The obtained pellet of fiber was washed with t-butanol and then t-butanol was added to the fiber to create a homogeneous suspension ([0292]). After centrifugation, the fiber was dried by lyophilization (freezing the fiber with liquid nitrogen and then applying a vacuum, see [0292]). The specification discloses that vacuum is applied to the frozen suspension until complete evaporation of the solvent occurs ([0292]). Figures 1A, 1C and 1E present the results of fibers obtained after purification and lyophilization with t-butanol, compared to analogous fibers lyophilized from water ([0293]). The specification further discloses that surface areas were determined from nitrogen adsorption data using the BET (Brunauer, Emmett, Teller) method ([0303]). The calculated surface area of SVX (spider silk protein expressed in bacteria) dried from t-butanol was about 180 m2/g, whereas the calculated surface area of SVX dried from water was about 85 m2/g ([0305]). Figures 1A, 1C, and 1E demonstrate via SEM images that the fiber is in the form of particles with a diameter ranging from 0.5 to 2 microns (see also [0031]).
In sum, the specification discloses a single species of the claimed genus of MaSp in the form of particles with a characteristic size ranging from 0.5 to 2 microns that are characterized by a BET surface area of 180 m2/g and a residual amount of t-butanol.
Arcidiacono et al. (Macromolecules 2002, 35, 1262-1266; cited in the Non-Final Action mailed on 5/13/2025) teaches aqueous processing and fiber spinning of recombinant spider silks: fibers were first spun into a coagulation bath containing methanol and water, after which the fibers were removed from the bath for evaluation (page 1263, left column, Fiber Spinning). However, Arcidiacono does not teach the BET surface area of the resulting fibers.
Roberts et al. (Molecules 25.5 (2020): 1207) teaches porous silk/activated-carbon composite fibers for adsorption and repellence of volatile organic compounds (Title). Roberts teaches reprocessing silkworm silk into aqueous regenerated silk fibroin (RSF) solutions before spinning into porous fibers via two cryogenic spinning techniques: Cryogenic Solution Blow Spinning (Cryo-SBS) and Cryogenic Wet Spinning (Cryo-WS) (paragraph 2 on page 2). By spinning colloidal suspensions of activated carbon (AC) in RSF, macroporous fibres loaded with AC can be obtained—increasing the specific surface area (SSA) (paragraph 2 on page 2). For the Cryo-WS method, RSF and colloidal RSF-activated carbon (AC) mixtures were wet-spun into an ethanol coagulation bath (page 3, 2. Results, paragraph 1, Figure 1(b)). The wet fibers were then subjected to solvent exchange in deionized (DI) water, before being rapidly frozen by submersion in liquid nitrogen followed by freeze-drying (page 3, 2. Results, paragraph 1). Roberts teaches in Table 1 the various BET surface areas for regenerated silk fibroin loaded with different wt% of activated carbon. The BET surface area of pure activated carbon is 697 m2/g, whereas 25% loading of the fiber results in 210 m2/g. Fiber without activated carbon (0 wt% AC) has a BET surface area less than 100 m2/g (Table 1). Roberts suggests the use of genetically engineered silks, such as recombinant spider silk, to tune the mechanical and textural properties of the silk or to introduce chemical functionality such as additional lysine groups to neutralize toxic VOCs or other substances (page 5, 3. Conclusions). However, Roberts produces thread-like porous particles that have a diameter 25-60 microns (Figure 1(d) and page 3, 2. Results, paragraph 1), which is distinct from the size of the presently claimed particles.
The prior art of Teagarden et al. (European Journal of Pharmaceutical Sciences 15.2 (2002): 115-133) teaches that tert-butanol/water is used as a co-solvent system in the freeze-drying of pharmaceutical products (Abstract). Teagarden teaches that one pharmaceutical product is manufactured by freeze-drying from a 20% v/v tert-butanol/water co-solvent system (page 115, right column, top paragraph). Teagarden teaches numerous reasons why freeze-drying with an organic solvent system can be desirable: the process increases rate of sublimation and decreases drying time, increases chemical stability of the pre-dried bulk solution, increases chemical stability of the dried product, increases drug wettability and solubility in solution, decreases reconstitution time, and enhances sterility assurance for pre-dried bulk solution (page 1515, right column, bottom paragraph). However, Teagarden also teaches that other co-solvent systems which do not freeze completely in commercial freeze-dryers were more difficult to use and often resulted in unacceptable freeze-dried cakes (Abstract). Teagarden teaches a variety of organic solvents evaluated in freeze-drying (Table 1) as well as systems with drug preparations freeze-dried from co-solvents (Table 2). The person of ordinary skill in the art would have been unable to predict based on the state of the art the effect of different mixtures of organic solvents comprising t-butanol on the BET surface area of a MaSp-based fiber.
Lyophilizing porous MaSp particles from a tert-butyl alcohol mixture (resulting in a residual amount of tert-butyl alcohol below 100 ppm) would have had an unpredictable effect on the surface area of the particles based on the state of the art.
Lu et al. (Cellulose 25.1 (2018): 619-629) teaches that freeze-drying fibrillated cellulose fiber from a water and TBA mixture results in the construction of a spider web-like structure because: (1) TBA molecules promote the separation of microfibrils and (2) the presence of TBA changes the morphologies and growth kinetics of ice-crystals (Abstract, right column). However, Lu’s fibrillated cellulose is a polysaccharide-based structure and does not comprise protein-based particles.
Teagarden et al. (European Journal of Pharmaceutical Sciences 15.2 (2002): 115-133; cited in the Non-Final Action mailed on 5/13/2025) teaches that TBA causes ice to form needle-shaped crystals and that as these needle-shaped crystals sublime, they create a more porous, less resistant matrix, which facilitates drying (bottom of left column on page 119 to top of right column on page 119). Teagarden also teaches that tert-butanol sublimes during primary drying and creates a porous structure, which facilitates the mass transfer of water vapor (left column on page 121). Teagarden teaches freeze-drying from a cosolvent such as TBA can improve drug product stability (page 123, left column, 5. Stabilization of freeze-dried product). However, Teagarden cautions that there are cases where the lyophilization of a protein from co-solvents can produce a less stable system (page 123, right column, second paragraph).
In sum, the person of ordinary skill in the art would have been unable to predict based on the state of the art the effect of liquids containing mixtures of organic solvents with tert-butyl alcohol on the surface area of porous MaSp particles prepared by freeze-drying.
Based on the above analysis, the person of ordinary skill in the art would not have recognized that the inventors were in possession of the claimed genus of MaSp particles comprising about 180 m2/g BET surface area and a residual amount of t-butanol less than 100 ppm. The person of ordinary skill in the art would not have recognized that the inventors were in possession of the claimed genus of drying methods capable of producing MaSp particles comprising about 180 m2/g BET surface area and a residual amount of t-butanol less than 100 ppm.
Examiner’s Comment
Applicant may consider amending the independent claims as follows in order to obviate the written description rejection of claims 1 and 13 under 35 U.S.C. 112(a) above.
1. A composition comprising a lyophilized porous major ampullate spidroin protein (MaSp) wherein said lyophilized MaSp is characterized by a Brunnauer-Emmet Teller (BET) surface area of about 180 m2/g and a residual amount of tert-butanol below 100 ppm; and wherein said lyophilized MaSp is in the form of particles having an average size in the range between 0.5 μm and 2 μm.
13. A method for obtaining a dried major ampullate spidroin protein (MaSp), the method comprising:
a. mixing a MaSp with t-butanol to obtain a mixture; and
b. removing said t-butanol
thereby obtaining said dried MaSp in the form of particles having an average size in
the range between 0.5 μm and 2 μm, wherein the dried MaSp is characterized by
BET surface area of about 180 m2/g, and by a residual amount of t-butanol
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.
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
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