DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Priority The present application, filed December 4, 2023, is a national stage application of PCT/CN2022/096315 , filed May 31, 2022, and claims priority to foreign priority application CN202110624071.9 , filed June 4, 2021. Status of the Application Applicant’s preliminary amendment, received June 4, 2024, wherein c laims 4, 7, 8, 9 and 10 are amended , cl aims 11-13 are cancelled , and n ew claims 14-20 are added, is acknowledged. C laims 1-10 and 14-20 are pending and examined on the merits herein . Claim Objections Claim s 4 and 6 are objected to because of the following informalities: Claims 4 and 6 recite “in a differential scanning calorimetry .” The examiner believes this to be a typographical error because differential scanning calorimetry , is a method, not an instrument, and suggests amending claims 4 and 6 to recite “when analyzed by differential scanning calorimetry” or similar. Appropriate correction is required. Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claims 15-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for a method for the treatment of a bone or joint disease comprising administering the crystalline form I or crystalline form II to a subject, such that the bone or joint disease is treated in the subject , does not reasonably provide enablement for prevention of a bone or joint disease comprising administering the crystalline form I or crystalline form II to a subject . The Applicant’s attention is drawn to In re Wands , 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman , 230 USPQ 546 ( BdApls 1986) at 547 the court recited eight factors: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. Nature of the invention : The invention s of claims 15 and 18 are drawn to method s for the prevention or treatment of a bone or joint disease comprising administering the crystalline form I according to claim 1 to a subject, or administering the crystalline form II according to claim 5 to a subject, such that the bone or joint disease is prevented or treated in the subject. Dependent claims 16-17 and 19-20 further limit the bone or joint disease to be prevented or treated. With respect to the definition of “prevention”, in the absence of an alternative definition of prevention provided by the specification, the claims are given their broadest reasonable interpretation. The Oxford English Dictionary defines the verb “to prevent” as “to preclude the occurrence of (an anticipated event, state, etc.); to render (an intended, possible, or likely action or event) impractical or impossible by anticipatory action; to put a stop to” (p. 8, definition II.9.a of “prevent”; cited in PTO-892). “Preventing” as recited in the instant application is thus interpreted to mean the complete and total blocking of all bone or joint diseases, for an indefinite period of time. Merely making these diseases less likely or less severe would not render the disease impossible and thus not qualify as preventing. The state of the prior art : The state of the art does not provide an expectation that bone or joint diseases may be rendered impossible by a nticipatory action. Lu (Publication no. US 20190185502 A1 ; cited in PTO-892) teaches working examples showing the efficacy of compound 16 (structure on p. 7, Table 1), which is the same compound as the compound of formula I of the present claims, for treating osteoarthritis and m edial me niscus t ransection . Lu teaches evaluation of compound 16 in a m onosodium i odoacetate- i nduced o steoarthritis (MIA) m odel in r at k ne e (p. 63, [0219]-[0220]). Lu teaches that t he results of their study indicate that osteophytes in the high dose group of compound 16 were significantly decreased compared with the vehicle group , and that the high dose - treated group showed a clear trend of lowering the mean values for each histological parameter evaluated in the study, including the Nature of Predominant Tissue, Surface Regularity, Structural Integrity, Chondrocyte Clustering, Degenerative Changes in Cartilage, Inflammatory Response in Subchondral Bone Region, and Neo-Vascularization. Lu teaches the lower morphological and numerical changes of chondrocytes and closer to normal nature of the tissue indicated that compound 16 slowed the articular cartilage degeneration in this MIA-induced OA rat model (p. 63, [0220]) (emphasis added). In addition, Lu teaches a s tudy of c ompound 16 in model of m edial me niscus t ransection (MMT) in ra ts . Lu teaches in the rat MMT model, the unilateral knee (right knee) was cleaned and prepped for surgery. An incision was made over the medial aspect of the femoro -tibial joint , and the medial collateral ligament was exposed via blunt dissection and transected to reflect the meniscus toward the femur. Lu teaches the joint space was returned to normal, and the skin was closed and the animal allowed to recover. Lu teaches that second day post - MMT induction, G1 and G2 animals were treatment with vehicle and test compound 16 respectively , dos ing by gavage 4 times every day for 4 weeks (p. 63, [0221]). Lu teaches that a fter MMT, weight bearing of the right paw was decreased sharply in both groups until d ay 3 , and that the rebounds of weight bearing on the right paw after day 3 were larger in G2 than in G 1 (p. 63, [0222] and Table 7; document p. 8, Figure 5). Lu further teaches histology data showed that the G2 group had values in all parameters lower than that of the G 1 group (p. 64, [0223] and Table 8; document p p . 9-10 , Figs. 6A-I). However, Lu does not teach administration of compound 16 as removing all symptoms of osteoarthritis and MMT. Therefore, on the effective filing date of the present application, one of ordinary skill in the art would have expected administration of compound 16 to treat bone and joint disease s by reducing the severity of symptoms and promoting recovery. However, one of ordinary skill in the art would not have expected administration of the compound of formula I to render bone or joint disease s impossible , and thus would not have expected that administration of a specific crystalline form of the compound of formula I would render bone or joint disease impossible. Moreover, prevention of a disease of a disease or disorder is not the same as treatment of said disease or disorder. In order to prevent a disease, as opposed to merely delaying or reducing symptoms, a method must either render the subject completely resistant to said disease after a limited number of treatments, or, when continued indefinitely, continue to suppress the occurrence of that disease. The prior art does not provide an expectation that administration of the compound of formula I would render bone or joint diseases impossible by anticipatory action. The relative skill of those in the art : The relative skill of those in the art is high. The predictability or unpredictability of the art : The lack of prior art disclosing the prevention of all bone and joint diseases means that one skilled in the art cannot predict the usefulness of a product or method to make these conditions possible. In addition, in view of the working examples disclosed by Lu and discussed above, one of ordinary sk ill in the art would have expected administration of a compound of formula I to treat bone and joint disease by reducing the severity of symptoms and promoting recovery. However, one of ordinary skill in the art would not have expected administration of the compound of formula I to render bone or joint disease impossible , and thus would have found a claim that bone or joint diseases may be prevented by administration of the compound of formula I to be unpredictable. Therefore , the invention of claims 15-20 is unpredictable. The breadth of the claims : The scope of the claims includes a method for the prevention or treatment of a bone or joint disease comprising administering crystalline form I according to claim 1 to a subject, or administering crystalline form II according to claim 5 to a subject, such that the bone or joint disease is prevented or treated in the subject. Prevention is defined in the above Nature of the Invention section. The amount of direction or guidance presented : The specification provides that the structure of a crystalline form of an active pharmaceutical ingredient often affects the chemical stability and other properties of the medication (for example, see pp. 1-2). However, the specification does not provide guidance on administering the compound of formula I for preventing bone or joint diseases, and thus does not provide enablement for the claimed therapeutic methods. The presence or absence of working examples : The specification provides working example s that are directed to methods of crystallization (e.g., Examples 1-6, pp. 9-15), which are not directly relevant to enablement of the claimed therapeutic methods and cannot provide enablement for the se therapeutic methods. In this instance, enablement instead must rely on the state of the prior art described above , which includes examples in which the compound of formula I is administered to a subject for the purposes of treating bone or joint disease. Note that lack of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art such as the prevention of bone and joint diseases in a subject by administering the compound of formula I. The quantity of experimentation required : In order to practice the invention o f the method for prevention of bone or joint diseases in a subject by administering crystalline form I or crystalline form II of the compound of formula I, one of ordinary skill in the art would be required to undertake a novel and extensive research program to show that said administration can render bone or joint diseases impossible. Because this research would need to be exhaustive, and because one may be required to develop a new model or new methodology showing that that the bone or joint disease is successfully prevented by administration of crystalline form I or crystalline form II of the compound of formula I , it would constitute an undue and unpredictable search burden. Genentech, 108 F.3d at 1366, sates that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.” Therefore, in view of the Wands factors, as discussed above, particularly the breadth of the claims and the nature of the invention, Applicants fail to provide information sufficient to practice the claimed invention of a method for prevention of bone or joint diseases in a subject by administering crystalline form I or crystalline form II of the compound of formula I . The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The term “ good solvent ” in claim 8 is a relative term which renders the claim indefinite. The term “good solvent” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For example, what specific properties are required of the “good solvent” recited in claim 8 for it to be classified as a “good solvent”? Claim 9 recites the term s good solvent and poor solvent, but claim 9 defines the good solvent as methyl tert-butyl ether and the poor solvent as heptane, and thus claim 9 is not indefinite. Allowable Subject Matter Claims 1-3, 5, 7, 9, 10, and 14 are allowed. In addition, c laims 4 and 6 are objected to for minor informalities, but would be allowed if these minor informalities were resolved . Claim 8 is rejected as indefinite, as described in the above rejection under 35 U.S.C. § 112(b), but would be allowed if those issues of indefiniteness were resolved. Claims 1-4, 7, and 10 are drawn to a crystalline form I of a compound of formula I, a method of making the crystalline form I , and a pharmaceutical composition comprising the crystalline form I and a pharmaceutically acceptable carrier . Claims 5-6, 8, 9, and 14 are drawn to a crystalline form I I of a compound of formula I, a method of making the crystalline form I I , and a pharmaceutical composition comprising the crystalline form II and a pharmaceutically acceptable carrier . The closest prior art to the crystalline forms I and II of the compound of formula I is considered Lu (Publication no. US20190185502A1 ; cited in PTO-892). Lu discloses the compound of formula I as compound 16 (p. 7, Table 1), and discloses a method of synthesizing compound 16 that concludes with hydrogenation of 1,3-O-dibenzyl-2-N-4,6-di-O-tributyryl-D- glucosamine catalyzed by Pd/C in methanol and acetic acid, followed by filtration and removal of solvent (concentration to dryness). Lu discloses that the product of this reaction was then purified by silica-gel column chromatography with M eOH/DCM to give compound 16 (synthesis on pp. 50-51, [0176]). The examiner notes that Kong (Publication no. US 20210079033 A1 ; cited in PTO-892) discloses the same synthesis of compound 16 (pp. 49-50, [0176]). Regarding the product of the synthesis taught by Lu as inherently having the form of crystalline forms I and II, Lu does not teach or suggest this product as having one or more specific crystal structures, and does not teach XRPD or DSC characterization of this product. The present specification provides that crystalline form I may be prepared by dissolving the product of f ormula I in acetonitrile , and subjecting this solution to a heating-cooling cycle comprising equilibrating at 25°C for 5 minutes , heating to 80°C at a rate of 1 °C/min and holding for 30 minutes , and then cooling to -20 °C at a rate of 1 °C/min and holding for 2 hours. The specification provides that wh en th is temperature program was completed, the vial was brought to room temperature and stirred overnight to obtain solid I ( crystalline form I) (p. 9, Example 1). The present specification provides that crystalline form II may be prepared by dissolving the product of Formula I in 2 ml of methyl tert-butyl ether to obtain a nearly saturated and clear solution, and subsequently adding 5 m l of heptane to the solution to induce precipitation. Following induction of precipitation, the suspension is slurried overnight and filtered to obtain a solid (crystallin e form II). Therefore, the method of making the compound of formula I disclosed by Lu requires a different method of isolating the reaction product ( isolation from MeOH and acetic acid following hydrogenation, and isolation from MeOH/DCM following purification by column chromatography) than the methods of preparing crystalline form I or crystalline form II disclosed by the present application. Thus t he product obtained by this method would not have been expected to inherently have the form of crystalline form I or crystalline form II as presently claimed. Regarding enablement of the presently claimed compounds and methods , because the present application discloses the methods above for preparing crystalline form I and crystalline form II of the compound of formula I , each of c rystalline form I and crystalline form II and the methods of making crystalline form I and crystalline form II are enabled by the specification. Conclusion Claims 1-3, 5, 7, 9, 10, and 14 are allowed. Claims 4 and 6 are objected to for minor informalities. Claims 8 and 15-20 are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT BENJAMIN BRANDSEN whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (703)756-4780 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday - Friday from 9:00 am to 5:00 pm . 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Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /B.M.B./ Examiner, Art Unit 1693 /ANDREA OLSON/ Primary Examiner, Art Unit 1693