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 .
Election/Restrictions
Applicant’s election of Group I (i.e., claims 1-15 drawn to a pharmaceutical composition comprising an isolated FVIII protein and/or an isolated VWF protein in a stabilizing buffer composition where the composition is free of albumin and further comprises cryoprotectants and bulking agents in a weight ratio of more than 0.65:1) in the reply filed on March 19, 2025, is acknowledged. Applicant’s election of Species A (i.e., a single and specific composition as containing both isolated FVIII functionally active fragment and VWF is a protein having an identity of at least 90% to SEQ ID NO: 3, sucrose in a concentration of mor than 23% (w/w) as a cryoprotectant, NaCl as a bulking agent, CaCl, sodium citrate, and poloxamer 188) in the reply filed on March 19, 2025, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Please note that Species A is expanded to include a composition containing only isolated FVIII and melezitose as a cryoprotectant in combination with calcium chloride and poloxamer 188 in light of the Examiner’s search.
Status of Claims
Claims 1-19 were originally filed on February 8, 2022.
The amendment received on February 8, 2022, amended claims 2-13 and 16-19. The amendment received on September 22, 2025, canceled claims 16-19; and amended claims 1-2 and 5-6.
Claims 1-15 are currently pending and are under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/EP2020/072919 filed August 14, 2020, and claims priority under 119(a)-(d) to European Application No. 19192137.8 filed on August 16, 2019.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for European Application No. 19192137.8, which papers have been placed of record in the file. Please note that the European application is in English and therefore no further action is necessary.
Response to Arguments
Applicant’s arguments, see Response, filed 9/22/25, with respect to 112(b) rejection have been fully considered and are persuasive. The rejection of claim 5 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 has been withdrawn.
Applicant’s arguments, see Response, filed 9/22/25, with respect to 112(b) rejection have been fully considered and are persuasive. The rejection of claim 7 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 has been withdrawn.
Applicant’s arguments, see Response, filed 9/22/25, with respect to 102(a)(1) rejection have been fully considered and are persuasive. The rejection of claims 1-8 and 13-15 as being anticipated by Ivarsson et al. WO 2011/131720 A1 published October 27, 2011 (cited in the IDS received on 2/8/22), alone or as evidenced by Pipe et al., J. Thromb. Haemost. 9:2235-2242 (2011) has been withdrawn.
Maintained/Modified Rejections Necessitated by Amendment
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 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 pre-AIA 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1-5, 9-10, and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Chapman et al. WO 2019/010497 A1 published on January 10, 2019 in view of Olsen et al. US Publication No. 2016/0207977 A1 published on July 21, 2016. Please note that the rejection has been updated in light of Applicants’ amendments to claim 1.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
For claims 1 and 3-4, with respect to a pharmaceutical composition comprising an isolated FVIII protein and an isolated VWF protein in a stabilizing buffer composition that is free of albumin and further comprises cryoprotectants and bulking agents as recited in instant claim 1; with respect to where the cryoprotectant is sucrose and the bulking agent is NaCl as recited in instant claim 3; and with respect to where the stabilizing buffer composition comprises sucrose in a concentration of more than 23% (w/w) as recited in instant claim 4:
Chapman et al. teaches administering a dose (note: same as a pharmaceutical composition) to a subject containing recombinant VWF (rVWF) and recombinant FVIII (rFVIII) (See Chapman, claim 1). As such, the teachings of Chapman satisfy the claim limitation with respect to a pharmaceutical composition comprising an isolated FVIII protein and an isolated VWF protein as recited in instant claim 1. Moreover, Chapman et al. teaches that the rVWF is contained in a formulation containing a buffer, a sugar and/or sugar alcohol, a stabilizer, a surfactant, and can further include sodium, histidine, calcium and glutathione (See Chapman, [0067], [00178], [00182]). In one aspect, Chapman et al. teaches that the rVWF formulations are lyophilized prior to administration (See Chapman, [0068], [00178]). A lyophilized formulation is, at least comprised of one or more of a buffer, a bulking agent, and a stabilizer (See Chapman, [0069], [00144], [00178]). An appropriate buffering agent is included to maintain the formulation within stable zones of pH during lyophilization (See Chapman, [00145]). Chapman et al. depicts excipient components of lyophilized protein formulations including buffers that maintain pH of formulation during lyophilization and upon reconstitution, tonicity agent/stabilizers such as cryoprotectants that protect proteins from freezing stresses and lyoprotectants that stabilize proteins in the freeze-dried state including polyols, sugars and polymers, bulking agents such as mannitol and glycine that are used to enhance product elegance and to prevent blowout, provides structural strength to the lyo cake, and surfactants such as polysorbate 20 and 80 that reduce aggregation during lyophilization (See Chapman, [00145], [00148], [00182]; Table 1). The role of formulation excipients is to provide stabilization against the stresses of manufacturing, shipping and storage (See Chapman, [00146]).
Chapman et al. teaches that citrate is a preferred buffering agent present at a concentration ranging from 0.1 mM to 500 mM (See Chapman, [00156]-[00157]).
One or more stabilizers are added to prevent or reduce storage-induced aggregation and chemical degradation (See Chapman, [00158], [00182]). Stabilizers include sucrose and NaCl where the stabilizers are present in a concentration of about 0.1 to 1000 mM (See Chapman, [00158], [00182]). In some embodiments, Chapman et al. teaches that NaCl is present in an amount less than 300 mM and sucrose is present in an amount of 0.5% to about 20% (w/w) (See Chapman, [00182]). Chapman et al. defines “about” as denoting an approximate range of plus or minus 10% from a specified value (See Chapman, [004010]). As such, about 20% (w/w) encompasses 22% (w/w) sucrose, which is close to the claimed concentration of sucrose of more than 23% (w/w) as recited in instant claim 4. A prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metal Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court held a proper rejection of a claim directed toward an alloy of having "0.8% nickel, 0.3% molybdenum, 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.) Therefore, the claimed concentration of sucrose would have been suggested to one skilled in the art given that the claimed sucrose concentration (i.e., more than 23% (w/w)) is close to the prior art sucrose concentration (i.e., about 20% (w/w)). Thus, the teachings of Chapman et al. are suggestive of the claim limitations with respect to where the stabilizing buffer composition comprises sucrose in a concentration of more than 23% (w/w) as recited in instant claim 4.
Additionally, although Chapman et al. teaches NaCl being utilized as a stabilizer instead of a bulking agent, the functional properties of NaCl are necessarily present. Pursuant to MPEP 2112.01(II), “[p]roducts of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Thus, since Chapman et al. teaches that NaCl can be included in the formulations as a stabilizer is sufficient.
Additionally, the inclusion of one or more stabilizers in the formulation would necessarily constituting a stabilizing buffer composition. However, even if Chapman et al. did not expressly disclose that the composition is a stabilizing composition, since Chapman et al. teaches a pharmaceutical composition containing every claimed structural limitation as recited in instant claim 1, the functional property (i.e., stabilizing buffer composition) of the instantly claimed composition and the known composition would necessarily be present. The claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). Therefore, teachings of Chapman et al. satisfies the claim limitation with respect to where the pharmaceutical composition is a stabilizing buffer composition as recited in instant claim 1.
A bulking agent such as mannitol can be incorporated in a concentration ranging from about 0.1 mM to 1000 mM (See Chapman, [00159], [00182]).
Surfactants such as polysorbate 20 and 80 are commonly used in protein formulations to prevent surface-induced degradation and/or to prevent surface related aggregation phenomenon during freezing and drying (See Chapman, [00161], [00164], [00182]). Chapman et al. teaches that a surfactant is present at a concentration ranging from 0.005 to 1.0 g/L (See Chapman, [00164]).
Chapman et al. teaches that salts can be added to the rVWF formulations at a concentration ranging from 0.1 to 500 mM, which often increase the ionic strength of the formulation that is important for protein stability, physical stability, and isotonicity (See Chapman, [00165]).
Chapman et al. further teaches that metal ions can be added to the formulations because they can catalyze physical and chemical degradation reactions in proteins (See Chapman, [00170]). In particular, Chapman et al. teaches that metal ions confer stability or increased activity in proteins such ad FVIII (See Chapman, [00171]). Calcium ions up to 100 mM increased stability of FVIII (See Chapman, [00171], [00182]).
Additionally, Chapman et al. does not indicate inclusion of albumin, and thus, it must follow that the composition is albumin free as recited in instant claim 1.
Therefore, teachings of Chapman et al. as a whole suggest a pharmaceutical composition comprising an isolated FVIII protein, an isolated VWF protein in a stabilizing buffer composition that is albumin-free comprising cryoprotectants and bulking agents as recited in instant claim 1, where the cryoprotectant is sucrose and the bulking agent is NaCl as recited in instant claim 3, and where the stabilizing buffer composition comprises sucrose in a concentration of more than 23% (w/w) as recited in instant claim 4.
For claim 1, with respect to where the molar ratio of the isolated VWF protein to the isolated FVIII protein is in the range of 2L1 to 10:1:
Chapman et al. teaches that the rVWF to FVIII ratio is about 1.5:0.8 including 1.5:1 (See Chapman, [00192]). Chapman et al. defines “about” as denoting an approximate range of plus or minus 10% from a specified value (See Chapman, [004010]). As such, the rVWF to FVIII ratio encompasses a range from 1.65:1.1. Although, Chapman et al. does not indicate whether the rVWF to FVIII ratio is a molar ratio, given the finite number of types of ratios between rVWF and FVIII, e.g., molar or weight ratio, an ordinary skilled artisan would be motivated, at a minimum to try, with a reasonable expectation of success to utilize a rVWF to FVIII ratio of 1.65:1.1 as a molar ratio in order to treat bleeding events in a subject. Furthermore, a rVWF to FVIII ratio of 1.65:1.1 is close to the claimed molar ratio of 2:1 as recited in instant claim 1. A prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metal Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court held a proper rejection of a claim directed toward an alloy of having "0.8% nickel, 0.3% molybdenum, 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.) Therefore, the claimed rVWF to FVIII molar ratio would have been suggested to one skilled in the art given that the claimed rVWF to FVIII ratio (i.e., 2:1 to 10:1) is close to the prior art rVWF to FVIII ratio (i.e., 1.65:1.1).
Additionally and/or alternatively, Olsen et al. teaches the co-administration of a rVWF and FVIII where such administration results in the FVIII molecules having a prolonged in vivo circulatory half-life with a surprisingly high bioavailability in connect with extravascular administration (See Olsen, [0010]). Olsen et al. also teaches a pharmaceutical composition thereof where preferred ratios of FVIII and VWF include FVIII/VWF ratios (molar ratios) of 0.5:1 to 1:50, such as e.g., 1:1 to 1:10 (See Olsen, [0065]). The optimal ratio between FVIII and VWF fragment in a co-formulation mixture may be determined by calculating the amount of bound FVIII:VWF at certain protein concentrations based on the binding affinity to the VWF variant for the FVIII species in question (See Olsen, [0065]).
Therefore, Chapman et al. teaches that the rVWF to FVIII ratio ranges from about 1.5:0.8 (See Chapman, [00192]). Olsen et al. teaches that the rVWF to FVIII molar ratio ranges from 1:1 to 10:1 where the molar ratio of the optimal ratio between FVIII and VWF fragment in a co-formulation mixture may be determined by calculating the amount of bound FVIII:VWF at certain protein concentrations based on the binding affinity to the VWF variant for the FVIII species in question (See Olsen, [0065]). As such, the molar ratio between VWF and FVIIII is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal molar ratio between VWF and FVIII needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to determine and adjust the amount of VWF and/or DVIII in order to achieve a molar ratio of 2:1 to 10:1 because an ordinary skilled artisan would have been able to utilize the teachings of Chapman et al. in combination with Olsen et al. to obtain various molar ratio parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the molar ratio between VWF and FVIII would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
For claims 1-2, with respect to where the cryoprotectants and bulking agents are present in a weight ratio of more than 0.65:1 as recited in instant claim 1; and with respect to where the weight ratio is in the range of 0.65:1 to 2.2:1 as recited in instant claim 2:
As discussed supra, Chapman et al. teaches that the rVWF formulations contain one or more stabilizers are added to prevent or reduce storage-induced aggregation and chemical degradation (See Chapman, [00158], [00182]). Stabilizers include sucrose and NaCl where the stabilizers are present in a concentration of about 0.1 to 1000 mM (See Chapman, [00158], [00182]). In some embodiments, Chapman et al. teaches that NaCl is present in an amount less than 300 mM and sucrose is present in an amount of 0.5% to about 20% (w/w) (See Chapman, [00182]). A bulking agent such as mannitol can be incorporated in a concentration ranging from about 0.1 mM to 1000 mM (See Chapman, [00159], [00182]). As such, the molar concentration of a stabilizer and bulking agent encompassed by Chapman are identical. However, the teachings of Chapman et al. do not expressly teach the weight amount of NaCl.
Therefore, Chapman et al. teaches that stabilizers are added to prevent or reduce storage-induced aggregation and chemical degradation (See Chapman, [00158], [00182]), stabilizers stabilize formulations against the stresses of manufacturing, shipping and storage (See Chapman, [00146]), and excipients are classified on the basis of the mechanisms by which they stabilize proteins against various chemical and physical stresses (See Chapman, [00146]). Chapman et al. also teaches that those skilled in the art will know what amount or range of excipient can be included in any particular formulation to achieve a biopharmaceutical formulation of the invention that promotes retention in stability of the biopharmaceutical (See Chapman, [00147]). Those skilled in the art will understand that the considerations described to specific excipients are equally applicable to all types of combinations of excipients (See Chapman, [00148]). The concentration of cryoprotectant and bulking agent in a weight amount thereby resulting in a ratio between the two excipients are clearly result specific parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal weight concentrations of the cryoprotectant and bulking agent thereby resulting in a ratio between the two excipients in the pharmaceutical composition needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to determine and adjust the weight concentration of a cryoprotectant and bulking agent in order to achieve a weight ratio as instantly claimed that stabilizes the rVWF pharmaceutical compositions because an ordinary skilled artisan would have been able to utilize the teachings of Chapman et al. to obtain various weight concentration parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the weight concentrations of a cryoprotectant and bulking agent thereby resulting in a weight ratio between the two excipients in the rVWF pharmaceutical composition would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
For claim 5, with respect to where the composition further comprises polysorbate 20 or 80 in a concentration in the range of 0.1 to 9% (w/w):
As discussed supra, Chapman et al. teaches that a lyophilized formulation is, at least comprised of one or more of a buffer, a bulking agent, and a stabilizer (See Chapman, [0069], [00144], [00178]). Chapman et al. depicts excipient components of lyophilized protein formulations including buffers that maintain pH of formulation during lyophilization and upon reconstitution, tonicity agent/stabilizers such as cryoprotectants that protect proteins from freezing stresses and lyoprotectants that stabilize proteins in the freeze-dried state including polyols, sugars and polymers, bulking agents such as mannitol and glycine that are used to enhance product elegance and to prevent blowout, provides structural strength to the lyo cake, and surfactants such as polysorbate 20 and 80 that reduce aggregation during lyophilization (See Chapman, [00145], [00148], [00182]; Table 1). The role of formulation excipients is to provide stabilization against the stresses of manufacturing, shipping and storage (See Chapman, [00146]).
Regarding a surfactant, Chapman et al. teaches that surfactants are commonly used in protein formulations to prevent surface-induced degradation (See Chapman, [00161]). Surfactants can also prevent surface related aggregation during freezing and drying (See Chapman, [00164]). Examples of surfactants to utilize in the rVWF formulations include polysorbate 20 or 80 (See Chapman, [00161]). For surfactants, the effective concentration for a given protein will depend on the mechanism of stabilization (See Chapman, [00163]). Chapman et al. also teaches that in the present formulations, the surfactant is incorporated in a concentration of 0.005 to 1.0 g/L (See Chapman, [00164]). However, Chapman et al. does not expressly teach the concentration of the surfactant as a % (w/w).
Since Chapman et al. teaches that surfactants such as polysorbate 20 or 80 are commonly used in protein formulations to prevent surface-induced degradation and/or prevent surface related aggregation during freezing and drying, and excipients are classified on the basis of the mechanisms by which they stabilize proteins against various chemical and physical stresses where the effective concentration for a given protein will depend on the mechanism of stabilization in a concentration ranging from 0.005 to 1.0 g/L, the concentration of surfactant in a weight percentage amount is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal weight percentage concentration of a surfactant such as polysorbate 20 or 80 in the pharmaceutical composition needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to determine and adjust the weight percentage concentration of a surfactant such as polysorbate 20 or 80 in order to stabilize the rVWF pharmaceutical compositions because an ordinary skilled artisan would have been able to utilize the teachings of Chapman et al. to obtain various weight percentage concentration parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the weight percentage concentration of a surfactant such as polysorbate 20 or 80 in the rVWF pharmaceutical composition would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
For claims 9-10, with respect to where the VWF protein consists of a VWF peptide and optionally one or more VWF fusion peptides as recited in instant claim 9; with respect to where the VWF peptide has an identity of at least 90% to a section of human VWF, where the section starts with amino acid 764 of SEQ ID NO: 2 and ends with an amino acid of SEQ ID NO: 2 in the range of 1200-2000 as recited in instant claim 10:
Chapman et al. teaches that rVWF can include all potential forms including the monomeric and multimeric forms (See Chapman, [0029]). The rVWF embraces any member of the VWF family including human VWF (See Chapman, [0030]) thereby necessarily constituting where the rVWF has the amino acid sequence of instant SEQ ID NO: 2 (i.e., human VWF). Chapman et al. also teaches that the amino acid sequence of the prepro-VWF is depicted as SEQ ID NO: 2 and the mature VWF protein is depicted as SEQ ID NO: 3, which corresponds to amino acids 764-2813 of the full length prepro-VWF amino acid sequence (See Chapman, [0086]). When comparing instant SEQ ID NO: 3 (note: is a fragment of instant SEQ ID NO: 2 constituting a section of human VWF starting with amino acid 764 and ends with an amino acid 1268) with Chapman’s SEQ ID NO: 3, there is 99.8% identity. Also embraces are mutants, variants, functional fragments and fusion proteins of the VWF proteins (See Chapman, [0030]). As such, the teachings of Chapman et al. satisfy the claim limitations with respect to where the VWF protein consists of a VWF peptide and optionally one or more VWF fusion peptides as recited in instant claim 9 where the VWF peptide is 99.8% identical to a section of the amino acid sequence of human VWF where the section starts with amino acid 764 of SEQ ID NO: 2 and ends with an amino acid of SEQ ID NO: 2 in the range of 1200 to 2000 as recited in instant claim 10.
For claims 13-15, with respect to where the pharmaceutical composition is a solution or a lyophilizate as recited in instant claim 13; with respect to where a ready-to-use solution for use in medical treatment which is reconstituted from a lyophilized pharmaceutical composition of claim 13 by the addition of an aqueous diluent as recited in instant claim 14; and with respect to where the treatment comprises subcutaneous or intravenous administration as recited in instant claim 15:
Chapman et al. teaches that the rVWF is contained in a formulation containing a buffer, a sugar and/or sugar alcohol, a stabilizer, a surfactant, and can further include sodium, histidine, calcium and glutathione (See Chapman, [0067]). In one aspect, Chapman et al. teaches that the rVWF formulations are lyophilized prior to administration (See Chapman, [0068], [00140]). The standard reconstitution practice for lyophilized material is to add back a volume of pure water or sterile water for injection (See Chapman, [0070]-[0071], [00142], [00179]). As such, Chapman et al. teaches preparing reconstituted rVWF compositions comprising the step of adding a diluent to a lyophilized rVWF composition (See Chapman, [0070], [0072], [00179], [00180]). This, the teachings of Chapman et al. satisfy the claim limitations with respect to where the pharmaceutical composition is a solution or a lyophilizate as recited in instant claim 13 and a solution that is reconstituted from a lyophilized pharmaceutical composition of claim 13 by the addition of an aqueous diluent as recited in instant claim 14. Although Chapman et al. does not expressly disclose that this reconstituted solution is ready-for-use in medical treatment, the Examiner would like to remind Applicants that the preamble recites a solution, and while the use of a descriptive clause, i.e., “[a] ready-to-use solution for use in medical treatment,” when referring to the contemplated use (i.e. “intended use”) of a claimed compound is proper, it is not a limitation and thus of no significance in determining the patentability thereof over the prior art, please refer to In re Thomas (CCPA 1949) 178 F2d 412, 84 USPQ 132. Therefore, the teachings of Chapman et al. satisfy the claim limitations as recited in instant claim 14.
Similarly, even though Chapman et al. teaches that the rVWF formulations are administered parenterally via subcutaneous or intravenous injections (See Chapman, [00131]), it is unnecessary for a prior art reference to teach this limitation because the intended use of the solution (i.e., administration subcutaneously or intravenously) does not state a condition that is material to patentability or provide a structural limitation that would further limit the claimed solution other than requiring the solution is in a form capable of being administered subcutaneously or intravenously. The court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case, the intended use of the solution (i.e., administration subcutaneously or intravenously) is an intended result of the claimed solution that gives little meaning and purpose to the structure of the claimed solution. Accordingly, claim 15 recites an intended use that does not render material to patentability.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.012)
Chapman et al. does not expressly teach a specific embodiment of a pharmaceutical composition comprising an isolated FVIII protein and an isolated VWF protein in a stabilizing buffer composition where the molar ratio of the isolated VWF protein to the isolated FVIII protein is in the range of 2:1 to 10:1, where the composition is albumin-free and comprises cryoprotectants and bulking agents in a weight ratio of more than 0.65:1 as recited in instant claim 1. However, the teachings of Chapman et al. cure this deficiency by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-4143)
With respect to a pharmaceutical composition comprising an isolated FVIII protein and an isolated VWF protein in a stabilizing buffer composition where the molar ratio of the isolated VWF protein to the isolated FVIII protein is in the range of 2:1 to 10:1, where the composition is albumin-free and comprises cryoprotectants and bulking agents in a weight ratio of more than 0.65:1 as recited in instant claim 1, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Chapman et al. and formulate a pharmaceutical composition as a single dose comprising an isolated rVWF protein and an isolated FVIII protein in a molar ratio that is adjusted from about 1.5:1 to a molar ratio of 2:1 to 10:1 in a stabilizing buffer comprising a cryoprotectant and a bulking agent as stabilizers in a weight ratio of more than 0.65:1 where the inclusion of the stabilizers stabilize the pharmaceutical composition by preventing or reducing storage-induced aggregation and chemical degradation as stresses of manufacturing, shipping and storage. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because rVWF pharmaceutical compositions were known to be administered as a single dose in combination with rFVIII to a subject and were known to be stabilized by adding stabilizers in a concentration ranging from 0.1 to 1000 mM as taught by Chapman et al.; and because pharmaceutical compositions comprising VWF and FVIII were known to be present in a molar ratio of 0.5:1 to 1:50, such as e.g., 1:1 to 1:10 in order to treat bleeding events in a subject as taught by Olsen et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the pharmaceutical composition comprising isolated rVWF of Chapman et al. was administered to a subject as a single dose in combination with isolated rFVIII where the rVWF and rFVIII are present in a ratio of about 1.5:1, and therefore, adjusting the ratio as a molar ratio from about 1.5:1 to 2:1 and formulating the pharmaceutical composition to include a cryoprotectant and bulking agent as stabilizers would support the prevention or reduction of storage-induced aggregation and chemical degradation as stresses of manufacturing, shipping and storage by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 1 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Chapman et al. WO 2019/010497 A1 published on January 10, 2019 in view of Olsen et al. US Publication No. 2016/0207977 A1 published on July 21, 2016, as applied to claims 1 and 5 above, and further in view of Gervasi et al., Eur. J. Pharm. Biopharm. 131:8-24 (2018), as applied to claim 5 herewith regarding calcium chloride, sodium citrate, and poloxamer 188 as elected by Applicants (See Election/Restriction section supra).
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
For claim 1, please see discussion of Chapman et al. and Olsen et al. supra.
For claim 5, with respect to where the composition further comprises calcium chloride in a concentration in the range of 0.2 to 4% (w/w), sodium citrate in a concentration in the range of 0.5 to 18% (w/w), and polysorbate 20 or 80 in a concentration in the range of 0.1 to 9% (w/w):
Regarding the inclusion of polysorbate 20 or 80, please see discussion supra. Additionally, as discussed supra, Chapman et al. teaches that a lyophilized formulation is, at least comprised of one or more of a buffer, a bulking agent, and a stabilizer (See Chapman, [0069], [00144], [00178]). Chapman et al. depicts excipient components of lyophilized protein formulations including buffers that maintain pH of formulation during lyophilization and upon reconstitution, tonicity agent/stabilizers such as cryoprotectants that protect proteins from freezing stresses and lyoprotectants that stabilize proteins in the freeze-dried state including polyols, sugars and polymers, bulking agents such as mannitol and glycine that are used to enhance product elegance and to prevent blowout, provides structural strength to the lyo cake, and surfactants such as polysorbate 20 and 80 that reduce aggregation during lyophilization (See Chapman, [00145], [00148], [00182]; Table 1). The role of formulation excipients is to provide stabilization against the stresses of manufacturing, shipping and storage (See Chapman, [00146]).
Regarding calcium chloride, Chapman et al. teaches that salts can be added to the rVWF formulations at a concentration ranging from 0.1 to 500 mM, which often increase the ionic strength of the formulation that is important for protein stability, physical stability, and isotonicity (See Chapman, [00165]). Chapman et al. further teaches that metal ions can be added to the formulations because they can catalyze physical and chemical degradation reactions in proteins (See Chapman, [00170]). In particular, Chapman et al. teaches that metal ions confer stability or increased activity in proteins such ad FVIII (See Chapman, [00171]). Calcium ions up to 100 mM increased stability of FVIII (See Chapman, [00171], [00182]). However, Chapman et al. does not expressly teach that calcium chloride is added to the formulation.
Regarding a buffering agent, Chapman et al. teaches that citrate is a preferred buffering agent present at a concentration ranging from 0.1 mM to 500 mM (See Chapman, [00156]-[00157]). An appropriate buffering agent is included to maintain the formulation within stable zones of pH during lyophilization and upon reconstitution (See Chapman, [00145]). However, Chapman et al. does not expressly teach that the buffering agent is sodium citrate.
Gervasi et al. reviews excipient components that are utilized in parenteral protein formulations that will stabilize proteins against stresses experienced during processing, storage, and administration (See Gervasi article, pg. 3, 1st paragraph). Excipients also aid reconstitution of lyophilized formulations, maintain sterility of multi-dose products, provide isotonicity, and in a small number of cases alter pharmacokinetics (See Gervasi article, pg. 3, 1st paragraph). Gervasi et al. teaches that coagulation factors represent the second largest class of therapeutic proteins that are manufactured only as lyophilized formulations (See Gervasi article, pg. 7, 4th paragraph).
Regarding calcium chloride, Gervasi et al. teaches that calcium chloride is usually employed as a complexing agent in lyophilized products containing coagulation factors (See Gervasi article, pg. 21, 1st paragraph). Coagulation factors are a class of therapeutic proteins whose activity and stability is promoted in presence of calcium ions (See Gervasi article, pg. 3, 1st paragraph). In Table III, Gervasi et al. teaches one approved protein formulation of human normal Ig containing calcium chloride in a concentration of 0.4 mg/ml (See Gervasi article, Table III). Thus, the teachings of Gervasi et al. suggest adding calcium chloride as a complexing agent in lyophilized products containing coagulation factors.
Therefore, Chapman et al. teaches that excipients are classified on the basis of the mechanisms by which they stabilize proteins against various chemical and physical stresses. Chapman et al. also teaches that those skilled in the art will know what amount or range of excipient can be included in any particular formulation to achieve a biopharmaceutical formulation of the invention that promotes retention in stability of the biopharmaceutical. Those skilled in the art will understand that the considerations described to specific excipients are equally applicable to all types of combinations of excipients (See Chapman, [00148]). In particular, Chapman et al. teaches that calcium ions up to 100 mM increased stability of FVIII. Gervasi et al. teaches that calcium chloride is usually employed as a complexing agent in lyophilized products containing coagulation factors. The concentration of calcium chloride in a weight percentage amount is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal weight percentage concentration of calcium chloride in the pharmaceutical composition needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to determine and adjust the weight percentage concentration of calcium chloride in order to achieve a weight ratio as instantly claimed that stabilizes the rVWF and/or FVIII pharmaceutical compositions because an ordinary skilled artisan would have been able to utilize the teachings of Chapman et al. and Gervasi et al. to obtain various weight percentage concentration parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the weight percentage concentration of calcium chloride in the rVWF pharmaceutical composition would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
Regarding a buffering agent, Gervasi et al. teaches the most common excipients in liquid and lyophilizes products in Table I where non-amino acid buffers are usually included in a range of concentrations between 0.2 to 14.8 mg/ml (usual ionic strength: 5-25 mM) (See Gervasi article, pg. 8, last paragraph). Buffers are required to adjust and maintain the pH to a value at which the specific protein has maximal stability (See Gervasi article, pg. 9, last paragraph). The most commonly used buffers in lyophilized protein products are sodium phosphate and sodium citrate (See Gervasi article, pg. 10, 2nd paragraph). In Table I, the concentration of sodium citrate ranges from 0.5 to 14.7 mg/ml (See Gervasi article, Table I). Thus, the teachings of Gervasi et al. suggest that sodium citrate is a commonly used buffer for lyophilized protein products.
Therefore, Chapman et al. teaches that citrate is a preferred buffering agent present at a concentration ranging from 0.1 mM to 500 mM where an appropriate buffering agent is included to maintain the formulation within stable zones of pH during lyophilization and upon reconstitution. Chapman et al. teaches that excipients are classified on the basis of the mechanisms by which they stabilize proteins against various chemical and physical stresses. Chapman et al. also teaches that those skilled in the art will know what amount or range of excipient can be included in any particular formulation to achieve a biopharmaceutical formulation of the invention that promotes retention in stability of the biopharmaceutical. Those skilled in the art will understand that the considerations described to specific excipients are equally applicable to all types of combinations of excipients (See Chapman, [00148]). Gervasi et al. teaches that the most commonly used buffers in lyophilized protein products are sodium phosphate and sodium citrate. In Table I, the concentration of sodium citrate ranges from 0.5 to 14.7 mg/ml. The concentration of sodium citrate in a weight percentage amount is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal weight percentage concentration of sodium citrate in the pharmaceutical composition needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to determine and adjust the weight percentage concentration of sodium citrate in order to achieve a weight ratio as instantly claimed that stabilizes the rVWF and/or FVIII pharmaceutical compositions because an ordinary skilled artisan would have been able to utilize the teachings of Chapman et al. and Gervasi et al. to obtain various weight percentage concentration parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the weight percentage concentration of sodium citrate in the rVWF pharmaceutical composition would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
Regarding poloxamer 188 as the surfactant, Gervasi et al. teaches that surfactants in both liquid and lyophilized formulations stabilize the protein, increasing its solubility and minimizing interface interactions (See Gervasi article, pg. 17, last paragraph). The main surfactants included in liquid and lyophilized products are polysorbate 20, polysorbate 80 and poloxamer 188 (See Gervasi article, pg. 18, 2nd paragraph). Gervasi et al. teaches that the amount of non-ionic surfactants normally ranges from 0.0003 to 0.3% (w/v) (See Gervasi article, pg. 18, 2nd paragraph). Poloxamers are seen as an alternative to the polysorbates (See Gervasi article, pg. 19, 2nd paragraph). Thus, an ordinary skilled artisan would substitute the polysorbate 20 or 80 as taught by Chapman et al. with poloxamer 188 as further articulated below.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.012)
Chapman et al. does not expressly teach where the composition further comprises calcium chloride, sodium citrate, and poloxamer 188 as recited in instant claim 5. However, the teachings of Chapman et al. and Gervasi et al. cure this deficiency by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art refere