Weiping Yu et al.Download PDFPatent Trials and Appeals BoardAug 9, 201911508324 - (D) (P.T.A.B. Aug. 9, 2019) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 11/508,324 08/23/2006 Weiping Yu 2437.0070001/JMC/JGM 1844 26111 7590 08/09/2019 STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C. 1100 NEW YORK AVENUE, N.W. WASHINGTON, DC 20005 EXAMINER GREENE, IVAN A ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 08/09/2019 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): e-office@sternekessler.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte WEIPING YU and JOHN MON 1 ____________ Appeal 2019-001234 Application 11/508,324 Technology Center 1600 ____________ Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and DEBORAH KATZ, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL The claims in this appeal are directed to a method of storing a frozen liposome formulation, where the liposomes comprise doxorubicin. The Examiner rejected the claims under 35 U.S.C. § 112 as indefinite and 35 U.S.C. § 103 as obvious. Pursuant to 35 U.S.C. § 134, Appellant appeals the Examiner’s determination that the claims are unpatentable. We have jurisdiction for the appeal under 35 U.S.C. § 6(b). The Examiner’s decision is AFFIRMED. 1 The Appeal Brief, filed Jul. 25, 2018 (“Appeal Br.”), lists Celsion Corporation as the real party in interest. Appeal Br. 3. Appeal 2019-001234 Application 11/508,324 2 STATEMENT OF THE CASE The claims stand finally rejected by the Examiner as follows: Claims 7, 8, 10–13, 39, 40, 47, 48, 50–53, 62 and 63 under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA), second paragraph, as indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. Ans. 3. Claims 7, 8, 10–13, 39, 40, 47, 48, 50–53, 62, 63, and 68 under 35 U.S.C. § 103(a) as obvious in view of Abra et al. (WO 2001/05372 A2; published, January, 2001) (“Abra”); Needham (US 6,726,925 B1, issued April, 2004) (“Needham”); Huang et al. (US 4,927,571; published May 22, 1990) (“Huang”); as evidenced by: Mihalko et al. (US 5,340,587, issued Aug. 23, 1994) (“Mihalko”): Avanti, Hydro Soy PC-Avanti Number 840058, http://www.avantilipids.com/index.php?, last visited June 2019 (“Avanti”); LECITHIN, Kirk-Othmer Encyclopedia of Chemical Technology, 1–17 (2000) John Wiley & Sons, Inc. (“Lecithin”); and product information for Phospholipon 90H (Phospholipid GmBH) (“Phospholipon”). Ans. 8–9. Independent claim 7, which is reproduced below, is illustrative of the claimed subject matter: 7. A method of storing a frozen liquid suspension liposome formulation having a) at least one phospholipid, at least one lysolipid chosen from monopalmitoyl phosphatidyl choline (MPPC), monolauryl phosphatidyl choline (MLPC), monomyristoyl phosphatidylcholine (MMPC), monostearoyl phosphatidylcholine (MSPC), and mixtures thereof, and at least one hydrophilic polymer chosen from DSPE- mPEG-2000, DSPE-mPEG-5000, and mixtures thereof, Appeal 2019-001234 Application 11/508,324 3 wherein the phospholipid is at least one phosphatidyl choline, and wherein the molar ratio of phospholipid to lysolipid is from about 80:20 to about 90:10, and wherein the hydrophilic polymer is an amount of 3 to 13 molar percent of total liposome lipids; and b) an encapsulated active agent that is doxorubicin, which method comprises freezing the liquid suspension liposome formulation to form a frozen liquid suspension liposome formulation and storing said frozen liquid suspension liposome formulation for at least one month, wherein % encapsulation of said active agent is substantially maintained over the period, and wherein there is no significant change in the liposome size of the formulation after thawing compared to the formulation prior to freezing. SECTION 112 REJECTION The Examiner found the following phrase in claim 7 to be indefinite: wherein % encapsulation of said active agent is substantially maintained over the period, and wherein there is no significant change in the liposome size of the formulation after thawing compared to the formulation prior to freezing. Substantially maintained Claims 7, 39, 40, 47, 62, and 63 recite that the percent encapsulation of the active agent is “substantially maintained” over the recited storage period. The Examiner found that the phrase is “indefinite” under pre-AIA 35 U.S.C. § 112, second paragraph and § 112(b) because the “metes and bounds” of the claims cannot be determined. Final Act. 3. Appellants contend: 1) that the term “substantially” has been found to be definite by the Federal Circuit Court of Appeals in numerous cases in which the term has been construed (Appeal Br. 8–9); 2) the term “substantially maintained” would be understood by one of ordinary skill in Appeal 2019-001234 Application 11/508,324 4 the art when read in the light of the Specification (Appeal Br. 7–9); and 3) the Specification “discloses methods for measuring the degree of encapsulation.” Appeal Br. 9. We have considered these arguments and do not find them persuasive. During patent examination proceedings, claim terms are given “the broadest reasonable meaning . . . in their ordinary usage as they would be understood by one of ordinary skill in the art, taking into account whatever enlightenment by way of definitions or otherwise that may be afforded by the written description contained in the applicant’s specification.” In re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997). Thus, while the term “substantially” may have been found to be definite in Deere & Co. v. Bush Hog, LLC, 703 F.3d 1349 (Fed. Cir. 2012) and Aventis Pharmaceuticals, Inc. v. Amino Chemicals Ltd., 715 F.3d 1363, 1377 (Fed. Cir. 2013) as asserted by Appellants (Appeal Br. 8), such determinations are not dispositive in this appeal. Indeed, in Aventis, the court specifically held that “same claim term can have different constructions depending upon the context of how the term is used within the claims and specification.” Aventis, 715 F.3d at 1373. The Specification must first be consulted to determine whether “substantially maintained” reasonably apprises the skilled worker of its meaning. The phrase “substantially maintained” does not appear in the Specification as it was originally filed. However, the Specification discloses that, in the past, “it has not been possible to effectively use freezing alone for the purpose of storing liposomes.” Spec. 7 (second full paragraph). The Specification states that “[a] formulation useful with the present invention Appeal 2019-001234 Application 11/508,324 5 can provide a composition wherein liposomes and nanoparticles can be frozen without damaging the membrane integrity or the encapsulated contents.” Id. The Specification further explains that the claimed hydrophilic polymer (“DSPE-mPEG-2000, DSPE-mPEG-5000”) “affords protection of the integrity of the liposome or nanoparticle membrane during freezing” and “maintains the properties of any compound entrapped or encapsulated within the nanoparticle or liposome.” Spec. 4 (last paragraph) (emphasis added). Thus, the Specification explains that the hydrophilic polymer recited in the claims protects the liposome during freezing and maintains the properties of the compound present in the liposome. We note that the term “maintains” is used in the Specification to describe the properties of the compound trapped in the liposome, the claim uses the term to describe how much of it is “maintained” in the liposome after freezing. The claims do not disclose a precise numerical value for how much “% encapsulation of said active agent” is necessary to meet the limitation that it be “substantially maintained over the [freezing] period.” However as explained in Sonix Technology Co., Ltd v. Publications International, Ltd., 844 F.3d 1370, 1377 (Fed. Cir. 2017): Because language is limited, we have rejected the proposition that claims involving terms of degree are inherently indefinite. Interval Licensing, 766 F.3d at 1370. Thus, “a patentee need not define his invention with mathematical precision in order to comply with the definiteness requirement.” Invitrogen Corp. v. Biocrest Mfg., L.P., 424 F.3d 1374, 1384 (Fed. Cir. 2005) (citation omitted). Indeed, “[c]laim language employing terms of degree has long been found definite where it provided enough certainty to one of skill in the art when read in the context of the invention.” Interval Licensing, 766 F.3d at 1370. Appeal 2019-001234 Application 11/508,324 6 Based on the ordinary meaning of “substantially”2 and “maintained,” 3 and the Specification disclosure discussed above, one of ordinary skill in the art would understand that the liposome is protected during freezing by keeping it largely, but not wholly, in its existing state. However, this meaning is not helpful by itself in apprising one of ordinary skill in the art of what actual values fall within the scope of the claim. The Specification provides examples of values that one of ordinary skill in the art would understand to fall within the scope of a “substantially maintained” percent encapsulation of doxorubicin. Specifically, the Specification discloses examples in which the liposomes were “stable” over a three-month period and “[n]o significant changes in . . . encapsulation [was] . . . observed over this time frame.” Spec. 12. Table 2 shows that at t=0, frozen liposomes showed 99.5% encapsulation of doxorubicin, and that after being frozen and thawed three times it was 99.4% at t=0, 99.5% at one- week, 99.5% at one-month, and 98.2% encapsulation at three-months. Spec. 13 (Table 2). While we do not limit the claims to these values,4 they do provide guidance as to what values represent “% encapsulation of said active agent is substantially maintained over the [storage] period.” 2 “[B]eing largely but not wholly that which is specified.” https://www.merriam-webster.com/dictionary/substantial (last accessed July 19, 2019). 3 “[To] keep in an existing state.” https://www.merriam- webster.com/dictionary/maintain (last accessed July 19, 2019). 4 Limitations from the Specification are not imported into the claims and “a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment.” SuperGuide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875 (Fed. Cir. 2004). Appeal 2019-001234 Application 11/508,324 7 As to values lower than those reported in Table 2, there is no helpful guidance in the Specification. The Specification teaches that the invention addresses “leakage problems” that occur during a freezing cycle. Spec. 2:1– 3; Appeal Br. 7–8. The Specification, however, does not teach unacceptable levels of leakage of the active agents nor leakage amounts that would be too high and not meet the limitation of “% encapsulation of said active agent is substantially maintained over the [storage] period.” In other words, the Specification does not compare the % encapsulation to liposomes with and without the hydrophilic polymer to determine what one of ordinary skill in the art would understand values of encapsulation when the liposomes are not protected during freezing. In the Reply Brief, Appellants argue that Abra “discloses methods for freezing and storing liquid liposome suspensions which result in a change in % encapsulation of 12% and 5% after only 1 month of storage at -20 °C.” Reply Br. 4. Appellants contend that “the claimed methods result in at least a 2-fold to 6-fold increase in storage stability.” Id. Thus, Appellants apparently rely on Abra to define an amount of active agent leakage that would not be considered by those skilled in the art to be a substantially maintained amount of encapsulated agent over the storage period. However, Appellants did not establish that the liposome formation in Abra possessed the leakage problem described in the Specification, i.e., that Abra’s liposomes are representative of the prior art liposomes that leaked active agent upon freezing. Appellants attempt to fill this gap by citing to the prior art “Doxil” formulation which Appellants contend has the same components as Abra’s liposomes. Reply Br. 4. However, while Doxil is disclosed in the Specification, and thus could be understood by one of Appeal 2019-001234 Application 11/508,324 8 ordinary skill in the art as possessing the stated leakage problem (Spec. 7 (second full paragraph)), Appellants did not provide adequate evidence that the Doxil disclosed in the Specification is the same formulation as the one described in Abra. Specifically, Abra discloses Doxil in its background section as containing sucrose, a cryoprotectant, to protect against freezing damage (Abra 2:16–20), but characterizes its own invention as liposomes suspended in a medium comprising a “water soluble salt and a cryoprotectant [such as sucrose], wherein the external medium has an outer osmolarity higher than the inner liposome osmolarity thereby establishing a lower inside/higher outside osmotic gradient across each liposome” (Abra 3:10–14; emphasis added). Appellants did not provide evidence that Doxil is suspended in such a medium. To the contrary, it appears that Abra considered its invention as a solution to the problem of prior art formulations, such as Doxil. Because Appellants did not establish by adequate evidence that the claimed liposome formulation is an improvement over the formulation described in Abra, we are not persuaded that the values described in Abra of a 5% and 12% change in encapsulation of the active agent upon freezing are necessarily excluded by the claims. We know that the values in Table 2 of the Specification fall within the claim scope, but the Specification does not apprise one of ordinary skill in the art how different the encapsulation values can be from those reported in Table 2 and still be within the scope of the claim, i.e., what is largely, but not wholly different from the values disclosed in the table. In sum, while we recognize that the phrase “substantially maintained” is a term of approximation that does not by itself render the claim indefinite Appeal 2019-001234 Application 11/508,324 9 under 35 U.S.C. § 112, we find that Appellants did not establish by adequate evidence how those of skill in the art would have construed the phrase in light of the Specification of the application involved in this appeal. No significant change Claim 7 also recited that “there is no significant change in the liposome size of the formulation after thawing compared to the formulation prior to freezing.” Claims 39, 40, 47, 62, and 63 have a similar limitation. The Examiner found the phrase to be indefinite because the phrase is “unclear”, “subjective”, and does not “allow the public to determine the scope of the claim.” Final Act. 4–5. Appellants argue that “the specification sets forth examples illustrating what constitutes a ‘significant change in liposome size of the formulation after thawing compared to the formulation prior to freezing.’” Appeal Br. 10. Appellants explain: As shown in Table 1 of the specification, the size of the doxorubicin loaded liposomes of the present invention (labeled as “Liposome with MPEG”) changed from 107 nm to 105 nm after 3 months, i.e., about 2% change in size, which is not a significant change. In contrast, the size of the doxorubicin- loaded liposomes that fall outside the claimed invention (labeled as “Liposome without MPEG”) changed from 121 nm to 137 nm after just 3 days, i.e., about 13% change in size. Appeal Br. 10. Thus, a 13% change is considered to be a significant change in size and excluded from the scope of the claim. Appellants also cite the disclosure in Table 2 of the Specification to support the interpretation of the disputed phrase: In addition, Table 2 of the specification lists the size of liposomes prior to freezing, thawed after 1 week of storage, Appeal 2019-001234 Application 11/508,324 10 thawed after 1 month of storage, thawed after 3 months of storage, and subject to three freeze-thaw cycles, being 97.0 nm, 98.9 nm, 96.7 nm, 97.8 nm, and 98.3 nm, respectively. The largest liposome size change is from 97.0 nm to 98.9 nm, i.e., a size increase of about 2%, which is not a significant change. Appeal Br. 10. The` Specification referred to the results in Table 2 as showing “[n]o significant changes in vesicle size, doxorubicin content, encapsulation or lipids content were observed over this time frame.” Spec. 12. Thus, based on the disclosure in the Specification showing values which show no significant change in vesicle size and those that do, we agree with Appellants that there is adequate evidence that the phrase “no significant change in the liposome size” when read in the light of the Specification reasonably apprises one of ordinary skill in the art of the scope of the claim. As to the Examiner’s objection to claim 47 because “(2) it is unclear whether the claim requires ‘at least two freeze-thaw cycles’, and if so when the ‘at least two freeze thaw cycles’ should be performed” (Final Act. 4), we find it would be clear to one of ordinary skill based on the plain language in the claim that the recited limitation is a property of the liposomes and does not have to be performed as part of the method. Summary The rejection under 35 U.S.C. § 112 of claims 7, 39, 40, 47, 62, and 63 is affirmed because the phrase “wherein % encapsulation of said active agent is substantially maintained over the period” does not reasonably apprise of ordinary skill in the art of the scope of the claim. Separate Appeal 2019-001234 Application 11/508,324 11 arguments for claims 8, 10–13, 48, 50–53, and 68 were not provided. Consequently, these claims fall as well. 37 C.F.R. 41.37(c)(iv)(1). REJECTION BASED ON ABRA Claim 7 is directed to a liposome formulation comprising a phospholipid, a lysolipid selected from a list of specific lysolipids, and a hydrophilic polymer selected from a list of specific polymers. Doxorubicin is encapsulated in the liposome. The claim recites that “the molar ratio of phospholipid to lysolipid is from about 80:20 to about 90:10, and wherein the hydrophilic polymer is an amount of 3 to 13 molar percent of total liposome lipid.” The Examiner found that Abra discloses a liposome composition having a resistance to freeze/thaw damage which comprises a phospholipid (hydrogenated soy phosphatidyl choline (“HSPC”)) and a hydrophilic polymer (mPEG-DSPE), meeting the corresponding limitations of claim 7. Final Act. 10. While Abra does not expressly recite that the liposome comprises a lysolipid, the Examiner provided evidence that a lysolipid is present in HSPC in the amounts required by the claim. Id. at 11–13. The Examiner also found that Abra also discloses that doxorubicin can be present in its liposome formulation. Id. at 15. The Examiner found that Needham discloses a liposome formulation with all three of the recited component in the same ratio as claimed. Final Act. 14 (citing Example 5 of Needham). The Examiner determined it would have been obvious to apply Abra’s freezing method to Needham’s liposome formulation because Abra disclose that “it is important that liposome preparations be stored for extended Appeal 2019-001234 Application 11/508,324 12 periods of time under appropriate conditions.” Final Act. 15. The Examiner found that “the low temperature would prevent the degradation of the composition while in storage; furthermore, storing the composition would provide a convenient means of managing the supply and demand of the manufactured product.” Id. at 15–16. Freezing Appellants contend that “that Abra’s attempts to prepare liposomes that are resistant to freezing damage were not successful.” Appeal Br. 17. Appellants state that “[t]herefore, Abra does not enable a person of ordinary skill in the art to successfully freeze and store liposomes, let alone liposomes with a different bilayer composition and a different active agent.” Id. at 18. Appellants state: However, while Abra may have considered freezing liposomes to be beneficial, a person of ordinary skill in the art would not have been motivated to do so by Abra, because Abra was not able to successfully freeze and store liposomes. As discussed above, Abra discloses that its liposomes were less stable (more leakage of cisplatin) when being stored at-20 °C as compared to being stored at +20 °C, or at 2-8 °C. Appeal Br. 19. Appellants also argue: Further, at the time of filing the present application, prolonged freezing (more than 1 month) was warned to have a deleterious effect on commercially available doxorubicin liposomes (see DOXIL ® labeling, a copy of which was submitted in our Reply and Amendment filed November 28, 2016 (Exhibit A)). The DOXIL ®liposomes contain mPEG-DSPE, HSPC, and cholesterol, the same components as Abra's liposomes. Thus, not only does Abra demonstrate that the liposomes are not stable for more than a month when frozen, a person of ordinary Appeal 2019-001234 Application 11/508,324 13 skill in the art would not have been motivated to store a frozen liquid suspension liposome formulation of doxorubicin over a prolonged period upon reading the DOXIL® labeling. Appeal Br. 18. This argument is not persuasive. First, Appellants did not provide persuasive evidence that Abra does not enable one of ordinary skill in the art to freeze and store liposomes. To support their argument, Appellants identify the data disclosed in Table 10 of Abra, stating that it “shows that the liposomes disclosed therein were less stable (i.e., more leakage of cisplatin) when being stored at -20 °C as compared to being stored at +20 °C or 2-8 °C.” Appeal Br. 15. The data in Table 10, as discussed by Appellants, show that the liposome stability at 20 °C and 2–8 °C is better than stability at freezing. However, Appellants overlook the fact that Abra does not show the results from the control which lacks the soluble salt and cryoprotectant said by Abra to protect the liposomes from freeze damage. Abra 3:10–14. Specifically, Abra lists a control in Table 9 which lacks sucrose, a cryoprotectant, and NaCl (the soluble salt), but did not disclose the results of freezing the control formulation in Table 10 which follows. Thus, it cannot be determined from the table, alone, whether Abra’s formulation comprising the cryoprotectant and salt in the disclosed concentrations is an improvement over the control, which lacks these protective agents. Appellants compare the room temperature results to the results obtained after freezing, but the proper comparison is between a control and the formulation comprising the salt and cryoprotectant, with both subjected to freezing to show how Abra’s method protects against freezing. The question is not whether the frozen liposomes are less stable than those at Appeal 2019-001234 Application 11/508,324 14 cold and room temperatures, but whether the salt and cryoprotectant protect the liposome formulation during freeze-thaw. While the data is not shown in Table 10, Abra makes numerous statements that a formulation comprising the soluble salt and cryoprotectant is protective against freeze-thaw damage. Following Table 10, Abra states: The stability tests indicate that a liposome composition having an osmotic gradient across the lipid bilayer, wherein the outer liposome osmolarity is higher than the inner osmolarity, provides additional protection from accidental freezing damage during product shipment, with negligible effect on product stability. Abra 20:7–11. The entire disclose of Abra is about resistance to freeze/thaw damage and improved protection upon freezing and thawing. Abra is titled “A liposome composition having resistance to freeze/thaw damage.” Abra 1:1– 2. See also 1:5–7; 2:23–26. Abra also specifically discloses that a liposome formulation comprising the salt and cryoprotectant showed improved freezing resistance in comparison to formulation with the cryoprotectant alone: In another aspect, the present invention provides a liposome composition having improved protection from freeze/thaw damage, as evidenced by a reduction in vesicle fusion and a reduction in the loss of entrapped contents, when compared to the protection provided by the presence of a cryoprotectant alone. Abra 2:27–3:2. Based on the explicit disclosure in Abra that the salt and cryoprotectant protect liposomes against freezing and Abra’s own comments on the data in Table 10, we find Appellants’ argument that Abra does not enable a liposome formulation to be protected against freeze-thaw to not be Appeal 2019-001234 Application 11/508,324 15 supported by the evidence in this record. Because this argument is the basis for Appellants’ contention that there would have been no reason to apply Abra’s method to Needham’s liposomes (Appeal Br. 15–16), we conclude that Appellants did not demonstrate that the Examiner erred in finding a reason to combine Abra and Needham. Expectation of success Appellants contend that a person of ordinary skill in the art would not have had a reasonable expectation of success of achieving the claimed invention. Appeal Br. 20. First, Appellants argue that the cisplatin described in Abra is a completely different molecule than doxorubicin recited in all the rejected claims and “thus ha[s] different chemical and physical properties.” Appeal Br. 20. Appellants state: For example, cisplatin has a water solubility of about 2 mg/ml at 37 °C, whereas doxorubicin has a water solubility of about 20 mg/ml at room temperature. As such, they have different affinities to the lipid membranes, and are formulated differently. Accordingly, a person of ordinary skill in the art would not have expected doxorubicin-containing liposomes to behave in the same manner as cisplatin-containing liposomes when frozen. Id. This argument does not persuade us that the Examiner erred. Abra expressly teaches that doxorubicin is an exemplary cytotoxic agent that can be entrapped in a liposome. Abra 23:3–6. Thus, while Abra’s working example is of a liposome with entrapped cisplatin (Abra 28:23), Abra expressly contemplated that liposomes comprising doxorubicin and other agents (id. at 23:4–29) would be protected against freeze-thawing utilizing a Appeal 2019-001234 Application 11/508,324 16 cryoprotectant and soluble salt. As explained by the Examiner, Abra “teaches that it is the osmolarity gradient between the liposome contents (inner medium) and the suspension medium (external medium) that is important in forming freeze/thaw stable liposome compositions not the active ingredient (abstract).” Ans. 19. Appellants did not provide adequate evidence that the active agent, itself, when incorporated into a liposome would change the ability of the cryoprotectant and salt to protect the liposome against freeze-thaw damage. Second, Appellants argue that Abra’s liposome formulations comprise cholesterol “which are drastically different from Needham's cholesterol-free liposome formulations.” Appeal Br. 20. Appellants provided a declaration under 37 C.F.R. § 1.132, by Francis C. Szoka (filed July 6, 2010, “Szoka Decl.”) “in which Dr. Szoka stated that the differences in chemical structure between cholesterol and phospholipids affect the rigidity and the permeability of liposome formulations containing them.” Appeal Br. 18. Based on the difference in properties, Dr. Szoka states: not only would a skilled scientist not have been able to predict that the liposome formulations of Tagawa (having cholesterol) and Needham (having phospholipids but no cholesterol) would behave in exactly the same way after freeze-thaw, i.e., retain the same amount of encapsulated drug, retain particle size, etc., he/she would not have been able to predict that the non-frozen liposomes formulations of Tagawa and Needham would behave in exactly the same way. Szoka Decl. ¶ 11. Dr. Szoka’s opinion is based a publication “Tagawa” which is not cited in the rejection in this Appeal. Dr. Szoka further states in his declaration that it was known that freezing would have a deleterious effect on Doxil, a commercially available Appeal 2019-001234 Application 11/508,324 17 liposome formulation comprising doxorubicin. Szoka Decl. ¶ 13. Dr. Szoka concludes that “skilled scientist would not have been motivated to freeze and store nanoparticle formulations for more than one month without risking adversely affecting the encapsulated drug product, based on the teachings of this document.” Id. Dr. Szoka further states in his declaration, citing the Fransen publication, that it is his opinion “that neither the cited references nor the knowledge in the art at the time the application was filed provides the skilled scientist with a reasonable expectation that one could successfully freeze and stably store nanoparticle formulations with the ingredients listed in the claims for a period of at least one month without adversely affecting the encapsulated drug product and without inducing significant changes in nanoparticle size and % of drug entrapment.” Id. ¶ 15. Dr. Szoka’s declaration is not persuasive. Dr. Szoka does not state in his declaration that the Abra publication was considered by him in making these statements about a lack of reasonable expectation of success. Abra is not listed in the publications said to have been considered by him in his declaration. Szoka Decl. ¶¶ 2, 5, 12. Dr. Szoka did not address the issue in the appealed rejection of whether Abra’s method of using a water soluble salt and cryoprotectant to protect against freeze-thaw would have been reasonably expected by one of ordinary skill in the art to protect Needham’s liposomes which lack cholesterol. The Doxil formulation, described by Dr. Szoka, is not cited in the current rejection. Consequently, Dr. Szoka’s opinions about the lack of a reasonable expectation of success is not persuasive because the actual prior art cited in the obviousness rejection in this appeal was not addressed. Appeal 2019-001234 Application 11/508,324 18 Abra, itself, does not limit its liposomes to the components exemplified in its examples, but refers generally to liposomes throughout its disclosure without identifying the specific components of them. The disclosure by Abra of its method of using protecting liposomes against freeze-thaw damage contains no limitation as to the composition of the liposomes. Abra 4:7–18. Rather, Abra describes its invention as relating to liposome compositions having “an osmotic gradient across the liposome lipid bilayer, wherein the suspension medium external to the liposome has a higher osmolarity than the osmolarity of the medium entrapped within the liposome.” Id. at 6:7–12. Thus, we find no evidence that a different liposome formulation than the one exemplified in Abra, would not have been reasonably expected to be protected against freezing utilizing Abra’s method. Unexpected results Appellants argue that the inventors “unexpectedly discovered that by practicing the claimed method, the encapsulation of doxorubicin (active agent) was substantially preserved over 3 months.” Appeal Br. 18. Citing Example 2 and Table 2 in the Specification, Appellants state that “after 3 months, the doxorubicin content of the liposomes only dropped from 99.5% encapsulation (frozen at t=0) to 98.2% encapsulation. (Application as-filed, pages 12-13, Table 2).” Id. Based on the labeling of Doxil, Appellants contend that one of ordinary skill in the art would have expected prolonged freezing to have a deleterious effect on a liposome preparation having the same components present in Abra’s liposomes, namely mPEG-DSPE, HSPC, and cholesterol. Id. Appeal 2019-001234 Application 11/508,324 19 Doxil is not the same liposome formulation as described in Abra. As discussed above, we have not been directed to evidence that Doxil contains the salt and cryoprotectant described in Abra as conferring resistance to freeze-thaw. To the contrary, it is disclosed in the background section of Abra that Doxil has a sugar for protection against freezing damage, but makes no mention of the soluble salt in the amounts necessary to achieve freeze-thaw resistance. Abra 2:16–20. Thus, we are not persuaded that one of ordinary skill in the art would have found it unexpected that liposomes could resist freezing damage, particularly when Abra provides a method to do so. Example 2 in the Specification shows the effect of freezing on a single liposome preparation comprising DPPC, MSPC, and DSPE-mPEG-2000. Spec. 11 (Example 1), Spec. 12 (Example 2), Spec. 13 (Table 2). However, there is no comparison to the closest prior art. When unexpected results are used to demonstrate the non-obviousness of a claimed invention, the results must be “surprising or unexpected” to one of ordinary skill in the art when considered in the context of the closest prior art. See In re Soni, 54 F.3d 746, 750; see also Iron Grip Barbell Co., Inc. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (A showing of “new and unexpected results” must be “relative to the prior art.”); In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are used as evidence of nonobviousness, the results must be shown to be unexpected compared with the closest prior art.”). Thus, here, Appellants did not compare the results to the closest prior art, namely, the Abra publication. In addition to this, unexpected results must be “commensurate in scope with the degree of protection sought by the claimed subject matter.” Appeal 2019-001234 Application 11/508,324 20 In re Harris, 409 F.3d 1339, 1344 (Fed. Cir. 2005). Appellants have only shown the results from a single liposome preparation, but the scope of the claim includes other liposome formulations that have have a different phospholipid, lysolipid, and hydrophilic polymer. Appellants did not demonstrate that the reported results would be obtained using other liposome formulations within the scope of the claim. Accordingly, we agree with the Examiner that Appellants’ evidence of the unexpected results is insufficient to establish the nonobviousness of the claimed subject matter. Summary The obviousness rejection of claim 7 is affirmed. Separate arguments for claims 8, 10–13, 39, 40, 47, 48, 50–53, 62, 63, and 68 were not provided. Consequently, these claims fall with claim 7. 37 C.F.R. 41.37(c)(iv)(1). TIME PERIOD No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Copy with citationCopy as parenthetical citation