METHOD OF SYNTHESIZING DENDRIMERIC AMPHIPHILE

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 . Election/Restrictions Applicant's election with traverse of the single disclosed species of the compound of Formula (IIb): PNG media_image1.png 131 204 media_image1.png Greyscale , wherein “M” is a rink amide resin, “X” is PNG media_image2.png 91 70 media_image2.png Greyscale , “Y” is Fmoc; the compound of Formula (IIIb): PNG media_image3.png 199 378 media_image3.png Greyscale , “B” is PNG media_image4.png 106 87 media_image4.png Greyscale , “B’” is PNG media_image5.png 65 64 media_image5.png Greyscale ; “n” = 0; “Z”: amino acids; the compound of Formula (IVb): PNG media_image6.png 218 406 media_image6.png Greyscale wherein “M” and “X” are as defined above; “K” is PNG media_image7.png 185 240 media_image7.png Greyscale wherein “B” and “B’” are as defined above; the compound of Formula (Vb): PNG media_image8.png 235 547 media_image8.png Greyscale ; “R’ “ is PNG media_image9.png 40 203 media_image9.png Greyscale ; wherein “X,” “K,” “B” and “B’” are as defined above; and in claim 4, “M” is a rink amide resin; in claim 9, the nitrite is iso-amyl nitrite; in claim 10, the polar solvent of step (b) is N,N-dimethyl-formamide; in claim 11, the hydrophilic solvent in step (c) is N,N-dimethylformamide; and in claim 12 the hydrophobic solvent in step (c) is dichloromethane; in the response to the restriction requirement, filed on July 2, 2026, are acknowledged. Regarding Applicant’s traversal, the instant claims are drawn to the preparation of an amphiphilic dendrimer according to formula (Vb) or (Vb’) which do not share a common core structure and therefore do not share a special technical feature. The requirement is still deemed proper and is therefore made FINAL. Drawings The drawings submitted October 31, 2023 are objected to because in Figures 4-11, the compounds and text of the reaction schemes are blurry and some of the heteroatoms, bonds, substituents, etc on the compound structures are difficult to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Specification The disclosure is objected to because of the following informalities: the chemical compound structures depicted on pages 11, 16 and 25, are blurry and difficult to read. Appropriate correction is required. Claim Objections Claim 6 is objected to for reciting “Benzy or Alloxycarbonyl [sic] groups” in lines 2-3, wherein each group is misspelled. The claim should recite: “benzyl, or alkoxycarbonyl groups.” Claim 8 is objected to because the chemical structures depicted are blurry and difficult to read, such that certain of the bonds and “R” variables are unclear. Appropriate correction is required. Claim Rejections - 35 USC § 112(b) 8. 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. 10. Claims 1-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 11. Claim 1 is rejected as being indefinite in the following aspects: (a) Claim 1 is unclear regarding the functional language recited in lines 3-5, i.e.: “…for replacing Y on the compound of formula (IIb) to develop branched skeletons, and modifying the terminal groups of the branched skeleton with functional moieties…”. It is not clear what is embraced by “to develop branched skeletons” or how said skeletons are developed. It is also not clear how said terminal groups are modified with functional moieties, or what is embraced by “functional moieties.” It is also noted that said recitation of the function language is verbose and superfluous, and should be deleted as follows: “A method for synthesizing an amphiphilic dendrimer, comprising: (a) reacting a compound of formula (IIb) with at least one diamino carboxylate having two protecting group (b) Claim 1 recites the limitation: "the terminal groups of the branched skeletons” in line 4, however there is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of “a terminal group(s) of the branched skeleton(s)” in the claim. (c) Claim 1 recites the limitation "the N-terminal of X” in line 10, however there is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of “an N-terminal of X” in the claim. It is also noted that the recitation of the functional limitation: “to protect the N-terminal of X” is superfluous and redundant. (d) Claim 1 recites the variable “K” in line 11, which is defined as “a moiety with branched diamine,” however this definition is confusing because it is not clear if K is a branched diamine moiety, or if K is a different moiety additionally comprising a branched diamine group. (e) Claim 1 recites the limitation: “provided that B is not the same as B’, at least one of Z, K or n of B is different from B’” in lines 15-16, which is confusing, because the variables Z, K and n are components within B’, and not the same as B’. If Applicant is intending to recite that at least one of the components Z, K and n of B differs from the components Z, K and n of B’, this limitation is redundant and superfluous because the claim requires the limitation that “B is not the same as B’”. (f) Claim 1 recites multiple instances of the variable “n” in the claim, each having a different definition, such that it is not clear which “n” is intended by Applicant in the last line of the claim. (g) Claim 1 is also indefinite regarding the limitation in step (c), line 6: “reacting at least two compounds of formula (IVb) with corresponding di- or multi-amine having hydrophobic residues,” because it is not clear what is embraced by “corresponding di- or multi-amine having hydrophobic residues,” i.e., is Applicant intending to recite di- or multi- amino groups, and it is not clear how said “di- or multi-amine” corresponds to the at least two compounds of formula (IVb). It is also not clear if the “at least two compounds of formula (IVb)” are the same or different. Clarification is requested. 12. Claim 3 depends from claim 1 and recites the limitation “…a compound having the X-Y” in lines 2-3, however there is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of “the X-Y” in claim 1 or in claim 3. 13. Claim 5 is rejected as being unclear in the following aspects: (a) Claim 5 depends from claim 1 and recites the limitation “wherein n is an integer, from 1 to 10;” in line 3. However, claim 1 also recites multiple instances of the variable “n” in the claim, each having a different definition, such that it is not clear which “n” is intended by Applicant in claim 5; (b) Claim 5 recites the limitation “…wherein PG is a protecting group to protect N, O, or S,” in the last line of the claim, which is confusing because it is unclear if “PG” refers to a protecting group previously recited in the claim, or if it refers to an additional, as-yet unrecited protecting group. (c) Claim 5 depends from claim 1 and recites the limitations “the O-PG derivatives,” “the S-PG derivatives,” and “the N-PG derivatives” in lines 6-8, however there is insufficient antecedent basis for these limitation in the claim because there is no prior recitation of “the O-PG derivatives” or “the S-PG derivatives” or “the N-PG derivatives” in claim 1 or in claim 5. It is also noted that the recitations: “the O-PG derivatives of,” “the S-PG derivatives of,” and “the N-PG derivatives of,” are redundant and superfluous and should be deleted from the claim. 13. Claim 7 is rejected as being unclear in the following aspects: (a) Claim 7 depends from claim 1 and recites the limitation: "the form of the B or B’ ” in line 1, however there is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of “the form of the B or B’ ” in claim 1; (b) Claim 7 recites the limitation: "the branched skeletons comprising KZ2, K(KZ2)2, K(K(KZ2)2)2, K(K(K(KZ2)2)2)2, or K(K(K(K(KZ2)2)2)2)2” in line 1, however there is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of “the branched skeletons comprising KZ2, K(KZ2)2, K(K(KZ2)2)2, K(K(K(KZ2)2)2)2, or K(K(K(K(KZ2)2)2)2)2” in claim 1. 14. Claim 8 depends from claim 1 and recites the limitation “wherein n is 0 to 20;” in the last line of the claim. However, claim 1 also recites multiple instances of the variable “n” in the claim, each having a different definition, such that it is not clear which “n” is intended by Applicant in claim 8. 15. Claim 13 depends from claim 1 and recites the limitation: "the reacting temperature” in line 1, however there is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of “the reacting temperature” in claim 1. 16. Claim 14 depends from claim 1 and recites the limitation: "the volume ratio of the hydrophilic solvent and the hydrophobic solvent” in line 1, however there is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of “the volume ratio of the hydrophilic solvent and the hydrophobic solvent” in claim 1. 17. Claim 15 is indefinite in the following aspects: (a) Claim 15 depends from claim 1 and recites the limitation: "the protecting groups of the compound of formula (Vb) or (Vb’)” in lines 2-3, however there is insufficient antecedent basis for this limitation in the claim because there is no prior recitation of “the protecting groups of the compound of formula (Vb) or (Vb’)” in claim 1. (b) It is also not clear how said protecting groups are removed in step (d), i.e., what specific method of deprotection under what conditions is/are intended to selectively remove said protecting groups, such that one of skill in the art would not know how to practice the method of step (d). 18. Claims 2-15 are also rejected as being dependent upon and including all of the limitations of rejected claim 1. Claim Rejections - 35 USC § 112(a) 19. 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. 20. Claims 1-15 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 the preparation of the elected amphiphilic dendrimer species of Formula (Vb): PNG media_image8.png 235 547 media_image8.png Greyscale , comprising reacting a compound of formula (IIb): PNG media_image1.png 131 204 media_image1.png Greyscale , wherein “M is a rink amide resin,” with the amino carboxylate “X”: PNG media_image2.png 91 70 media_image2.png Greyscale , wherein “Y” is Fmoc, to obtain a compound of formula (IIIb): PNG media_image3.png 199 378 media_image3.png Greyscale , wherein “K” is PNG media_image7.png 185 240 media_image7.png Greyscale and “Z” is an amino acid; wherein “B” is PNG media_image4.png 106 87 media_image4.png Greyscale , “B’” is PNG media_image5.png 65 64 media_image5.png Greyscale ; then reacting the compound of formula (IIIb) with a nitrite (iso-amyl nitrite) in a polar solvent (N,N,-dimethylformamide) to obtain a compound of formula (IVb): PNG media_image6.png 218 406 media_image6.png Greyscale , then reacting the compound of formula (IVb) with an amine having a hydrophobic residue in a mixed solution containing the hydrophilic solvent N,N-dimethyl-formamide and the hydrophobic solvent dichloromethane to obtain a compound of formula (Vb): PNG media_image8.png 235 547 media_image8.png Greyscale , and those embodied by the instant Specification, is not considered enabled for a method(s) of preparing all of the other amphiphilic dendrimer species embraced by the claims, as recited. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. 21. As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), the standard to be applied when determining enablement is achieved by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below. 22. Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.” In the instant case, the claimed invention pertains to the synthesis of any amphiphilic dendrimer according to formula (Vb) or (Vb’) according to the process of claim 1, wherein the Specification alleges said dendrimers are useful as conjugates/carriers for compounds such as drugs, imaging agents, and genes (paragraph [0002]). 23. The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” 24. As discussed above, the instantly claimed invention pertains to the synthesis of an amphiphilic dendrimer according to the process set forth in claim 1. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that - due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc) would interact with the given target to elicit a related biological response. 25. Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan’s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure-based drug design relies on knowledge of the three-dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation. 26. The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure-based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Anderson, page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Thiel, page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised. This is certainly true in the case of amphiphilic dendrimers which, as disclosed by Ni et al. (Nature Reviews Chemistry 2026), demonstrate significant challenges and altered activity following minor modifications to the surface: “Numerous studies on dendrimer surface modification have reported partial functionalization of the terminal groups, whereby distinct fractions of the periphery are endowed with different functionalities — for example, one subset of terminals rendered cationic, while others are PEGylated or conjugated with targeting and functional entities15. Although such strategies expand the chemical versatility of dendrimers, they substantially increase structural complexity. This heterogeneity complicates rigorous structural characterization, challenges the maintenance of molecular integrity and ultimately hampers precise and reproducible dendrimer engineering, in particular for higher-generation dendrimers.” (page 627, right column, second paragraph). 27. The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification discloses the synthesis of less than ten amphiphilic dendrimers wherein “M” is generically identified as a solid support material: generation-1 having a lysine core (Figure 4), generation-2 having a lysine core (Figure-5), generation-3 having a lysine core (Figure 6), generation-4 having a lysine core (Figure 7), hybrid generation-1 (Figure 8), and hybrid generation-2 dendrimer (Figure 9). Thus, support cannot be found for the preparation of the entirety of the scope of dendrimers and alternatives embraced by the formula of the instant claims. 28. Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “when a compound or composition claim is not limited by a recited use, any enabled use that would reasonably correlate with the entire scope of that claim is sufficient to preclude a rejection for nonenablement based on how to use” (emphasis added). For purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation.” 29. As to the first inquiry, as discussed above, the claims are drawn to the preparation of any amphiphilic dendrimer embraced by the genus of formulae (Vb) or (Vb’), according to the process recited in claim 1. Considering that said genus of amphiphilic dendrimers to be prepared is virtually without limit, i.e., the genera of compounds of formula (Vb): PNG media_image10.png 100 103 media_image10.png Greyscale or of formula (Vb’) PNG media_image11.png 125 122 media_image11.png Greyscale have not been limited at all by claim 1, such that R’ and R” embrace any amino group(s) or branched di- or multi-amino groups containing hydrophobic residues, X includes any amino carboxylate, K is any moiety with branched diamine, and both B and B’ comprise any functional moiety selected from H, any/all amino acid(s), any/all peptide(s), any/all acid(s), any/all sugar(s), any/all targeting ligand(s), any/all imaging molecule(s), any/all therapeutic agent(s), or any/all peptidomimetic molecule(s), without limit, it is evident that the genus of functional moieties alone embraced by the claims is extremely broad and has substantial variance. Furthermore, the generic recitation of functional moieties reaches through and embraces any future ligands possessing targeting ability, any future molecules possessing imaging ability, any future compounds/agents possessing therapeutic activity, and any future molecules possessing peptidomimetic activity, without limit. Thus, the scope of amphiphilic dendrimers embraced by the claims is virtually without limit, embracing hundreds of millions of potential dendrimers, if not billions, thus it is evident that the claims are broad. Yet, as discussed above, the instant Specification discloses the preparation of less than 10 amphiphilic dendrimers. As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below. 30. Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to an n generation dendrimer which are alleged by the Specification to act as anti-inflammatory agents. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of the scope of dendrimers with respect to the disclosure since the claims presently encompass hundreds of millions of compound species, and potentially billions of compound species, whereas the instant Specification discloses the preparation of less than ten such dendrimers. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds of millions of dendrimers, if not billions, encompassed by the claims that could be prepared based on the limited disclosure of less than 10 synthesized amphiphilic dendrimers. Given the unpredictability of amphiphilic dendrimers in particular, as evidenced by Ni et al. it is highly unpredictable whether any compound within the genus amphiphilic dendrimers identified by rational drug design based on the instant disclosure could, in fact, be prepared using the instant claimed process. Whether the other dendrimers (i.e., those not identified by rational drug design based on the instant disclosure) could be prepared is even less predictable. As such, the only way to ascertain which of the hundreds of millions, and potentially billions, of claimed dendrimers encompassed by the claims could be synthesized based on the limited disclosure would require undue experimentation. As such, claims 1-15 are rejected. 31. Claims 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement regarding the full scope of amphiphilic dendrimers according to the genera of formula (Vb) or (Vb’). The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. In particular, support cannot be found for the full scope of dendrimer compounds to be synthesized of formula (Vb): PNG media_image10.png 100 103 media_image10.png Greyscale or of formula (Vb’) PNG media_image11.png 125 122 media_image11.png Greyscale as instantly recited by the claims. 32. The MPEP §2163 states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), which notes that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, “not a mere wish or plan for obtaining the claimed chemical invention.” While the court recognizes that, “[i]n claims involving chemical materials, generic formulae usually indicate with specificity what the generic claims encompass” (Id.), it is also recognized that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim and/or the genus must be sufficiently detailed to show that applicant was in possession of the claimed invention as a whole (see Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991)). If a genus has substantial variance, the disclosure must present a sufficient number of representative species that encompass the genus in order to adequately describe the genus (i.e., the disclosure must describe a sufficient variety of species to reflect the variation within that genus). See MPEP § 2163. Otherwise, as stated by the court in Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company (Fed. Cir. 2010), “a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the applicant has invented species sufficient to support a claim to a genus. The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result. But the specification must demonstrate that the Applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” In this case, both B and B’ comprise any functional moiety selected from H, any/all amino acid(s), any/all peptide(s), any/all acid(s), any/all sugar(s), any/all targeting ligand(s), any/all imaging molecule(s), any/all therapeutic agent(s), or any/all peptidomimetic molecule(s), without limit. Furthermore, the generic recitation of functional moieties reaches through and embraces any future ligands possessing targeting ability, any future molecules possessing imaging ability, any future compounds/agents possessing therapeutic activity, any future molecules possessing peptidomimetic activity, and any future material possessing solid support ability (i.e., “M”), without limit. The claim fails to limit any of M, B, B’, or the protecting group Y, let alone the functional moiety “Z” in its entirety, such that each moiety is entirely defined by functional language (i.e., what the moiety does, rather than what specifically is embraced by the moiety). 33. The factors considered in the Written Description requirement are: (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and (5) the method of making the claimed invention. 34. Level of skill and knowledge in the art: The level of skill to practice the art of the instantly claimed invention is high and requires a variety of skills usually found in institutions and companies that employ highly trained and skilled scientists to carry out these tasks. 35. Partial structure; Physical and/or chemical properties; and Functional characteristics: The claims are drawn to the preparation of an amphiphilic dendrimer according to the extremely vast genera of formula (Vb): PNG media_image10.png 100 103 media_image10.png Greyscale or of formula (Vb’): PNG media_image11.png 125 122 media_image11.png Greyscale which breadth have not been limited at all by claim 1, such that R’ and R” embrace any amino group(s) or branched di- or multi-amino groups containing hydrophobic residues, X includes any amino carboxylate, K is any moiety with branched diamine, and both B and B’ comprise any functional moiety selected from H, any/all amino acid(s), any/all peptide(s), any/all acid(s), any/all sugar(s), any/all targeting ligand(s), any/all imaging molecule(s), any/all therapeutic agent(s), or any/all peptidomimetic molecule(s), without limit. In the instant case, it is evident that the genera of compounds embraced by formula (Vb) or by formula (Vb’) has substantial variance. The claimed genera are virtually without limit, embracing hundreds of millions of compounds, and potentially billions of amphiphilic dendrimers comprising functional moieties, which bear little to no structural overlap with one another whatsoever. Furthermore, the generic recitation of the functional moieties embraced by Z reaches through and embraces any future ligands possessing targeting ability, any future molecules possessing imaging ability, any future compounds/agents possessing therapeutic activity, and any future molecules possessing peptidomimetic activity, without limit. 36. The instant Specification alleges the dendrimers prepared by the recited synthesis are useful as conjugates/carriers for compounds such as drugs, imaging agents, and genes (paragraph [0002]). 37. Method of making: It is evident that the genus of compounds embraced by the claims has substantial variance, for example, the M, B, B’, or the protecting group Y, and functional moiety “Z” are virtually without limit and are only defined using functional language, such that the scope of dendrimers of formula (Vb) or formula (Vb’) recited by claim 1 embraces hundreds of millions of dendrimer species, if not billions of dendrimer species. Yet, the instant Specification demonstrates the synthesis of less than 10 dendrimer species according to formulae (Vb) or (Vb’) in Figures 4-10. 38. While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic claim. For example, in In re Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d 1008 (Fed. Cir. 1989). In the instant case, it is similarly determined that the disclosure of the preparation of less than 10 dendrimers does not adequately describe a genus embracing hundreds of thousands of millions of possible amphiphilic dendrimers comprising nearly any functional moiety “Z”. That is, the Specification does not disclose a sufficient variety of species to reflect the breadth of the possible compound selections recited in the claims. 39. The level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172; Capon v. Eshhar, 418 F.3d 1349, 1357-58, 76 USPQ2d 1078, 1083-84 (Fed. Cir. 2005). The fields of biology and chemistry are considered “unpredictable” because the complexity and unpredictability of chemical and biological interactions can make it difficult to understand the exact properties of an invention. A person of ordinary skill in the art from the specification or from the prior art cannot predict the pharmacological effects of administration of the instant formulation in subjects in regards to prevention of pain. The pharmaceutical industry is the prototypical example of a highly unpredictable field. Pfizer v. Teva Pharm., 482 F.Supp.2d 390, 413 (D.N.J. 2007); 2 Chisum on Patents §5.04. 40. Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure to use the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.” Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). 41. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521,222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). 42. Accordingly, it is deemed that the specification fails to provide adequate written description for the genera of amphiphilic dendrimers embrace by the claims in formula (Vb) and/or formula (Vb’) and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention. As such, claims 1-15 are rejected. Conclusion 43. In conclusion, claims 1-15 are pending, and all claims are rejected. No claim is presently allowed. 44. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST. 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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. /JANET L COPPINS/Examiner, Art Unit 1628 /AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628