DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2 Applicant's amendment, filed on 09/22/2023, is acknowledged.
3. Claims 1-4, 6, 8-10, 12-17, 19, 20, 23, 25, 29 and 30 are pending.
4. Applicant’s election with traverse of Group I, claims 1-4, 6, 8-10, 12-17, 19, 20, and 23 directed to a bispecific antibody that bispecifically binds to PD-LI and CD47,
filed on 7/2/2026, is acknowledged.
Applicant’s traversal is on the grounds that Solovyev fails to disclose or suggest the specific structural layout of the bispecific antibody defined in claim 1 of the present application. Specifically, claim 1 defines the claimed subject matter to a unique "Dual-VHH" layout comprising a "first single domain antibody (first sdAb)" and a "second single domain antibody (second sdAb)." This precise, non-generic structural configuration is structurally distinct from the standard antibody formats or alternative fragments generic to the teaching of Solovyev and thus, constitutes a clear structural differentiation.
Moreover, this unique structural configuration of the bispecific antibody of the present
application achieves unexpected, markedly superior physiological results that define a "special
technical feature" under 37 CFR § 1.475. First, with respect to safety, it completely overcomes
the notorious side effect of conventional anti-CD47 antibodies, which induces severe anemia due
to red blood cell (RBC) binding. The experimental data provided in the specification explicitly
demonstrates that absolutely no RBC binding or hemagglutination was observed even at a
maximum concentration of 3 µM. See, Specification, Figures 8 and 9. Second, with respect to
efficacy, the claimed antibody demonstrated exceptional potency in activating macrophage
phagocytosis and achieved unparalleled tumor volume reduction in robust in vivo mouse models.
See, id., Figures 7, 10, and 11.
This not found persuasive because Solovyev teaches and claims a bispecific antibody which specifically binds to CD47 and PD-L1, wherein the binding site of the CD47 and PD-L1 is VHH (i.e., sdAb). Importantly, evidence of secondary considerations, such as teaching away, unexpected results or commercial success, is irrelevant to 35 U.S.C. 102 rejections and thus cannot overcome a rejection so based. In re Wiggins, 488 F.2d 538, 543, 179 USPQ 421, 425 (CCPA 1973). As such, Applicant’s arguments regarding that unexpected, markedly superior physiological results are irrelevant to the anticipatory rejections.
Since Applicant elects Group I, the species election for Group III is moot.
The requirement is still deemed proper and is therefore made FINAL.
5. Claims 25, 29 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
6. Claims 1-4, 6, 8-10, 12-17, 19, 20, and 23 are under examination as they read on a bispecific antibody that bispecifically binds to PD-LI and CD47.
7. Applicant’s IDS, filed 08/18/2023, is acknowledged.
8. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
9. Claims 12-14 and 20 are rejected under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 4 recite “comprising at least one or more amino acid substitutions” in the bispecific antibody that bispecifically binds to PD-L1 and CD47 of claim 1, however claim 1 recites anti-PD-L1 sdAb and anti-CD47 sdAb, no variations/modifications are recited in claim 1. Thus claim 12 broaden the scope of claim 1. Similarly claim 20 which depends from claim 15. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
10. The following is a quotation of 35 U.S.C. 112(b) (Pre AIA , 35 U.S.C. 112, second paragraph):
(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.
11. Claims 2-4, 6, 8-10, 19 are rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
i) “Represented by” in claims 2-4, 6, 8-10, 19 implies any member of a genus that is “represented by” the respective SEQ ID NO:. Such language fails to establish the metes and bounds of amino acid encompassed by the instant claim language; therefore the claims are indefinite.
ii) “Preferably” in claims 4, 6, 10, 15, is indefinite because the narrow range within the broad range using the term “preferably” renders the claim indefinite.
(ii) the recitation “the peptide linker . . . represented by SEQ ID NO: 11” in claim 10 is indefinite because SEQ ID NO: 11 is not a peptide linker. SEQ ID NO: 11 is a fusion of anti-PD-L1/CD47 bispecific comprising anti-CD47 SdAb fused anti-PD-L1 SdAb via linker.
12. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
13. Claims 1-4, 6, 8-10, 12-17, 19, 20, and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 4, 6 10, 15-17 and 23 encompass a broad genus of bispecific antibody that bispecifically binds to PD-L1 and CD47 nanobodies.
Claims 2 and 8 encompasses a broad genus of anti-PD-L1 sdAb.
Claims 3 and 9 encompasses a broad genus of anti-CD47 sdAb.
Claims 12-14, 20 encompass a genus of sdAb modifications comprising at least one o more amino acid substitutions.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of bispcifically bind to PD-L1 and CD47. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The specification under example 1 discloses that human PD-L1 protein or human CD47 protein as an immune antigen was mixed with an immune adjuvant (GERBU), and one alpaca was inoculated with the mixture three times by intramuscular injection for immunization. [0197]. [0198] An immune library was constructed by amplifying a gene encoding a single domain antibody that bound to the immune antigen identified in Example 1.
Example 7 discloses that one single domain antibody that specifically binds to each of the PD-L1 and CD47 antigens was selected, respectively. The nucleotide sequences encoding the respective single domain antibodies were linked using a peptide linker, and two single domain antibodies specifically binding to PD-L1 and a single domain antibody specifically binding to CD47 were sequentially linked (anti-PD-L1 sdAb×anti-PD-L1 sdAb×anti-CD47 sdAb). The nucleotide sequence encoding such a trivalent bispecific single domain antibody was obtained through gene synthesis (Macrogen, Korea). For the expression and purification of a bispecific single domain antibody having a human IgG4 Fc domain fused thereto, the synthesized gene was cloned into a TGEX-Fc (IgG4) expression vector, and expression and purification were performed in the same manner as described in Example 1-6.
[0256] As a result, as presented in Table 17, the anti-PD-L1×CD47 trivalent HCAb (PPC Nb-IgG4) has been confirmed to have an excellent affinity of 6.84 nM for the PD-L1 antigen and 3.62 nM for the CD47 antigen.
[0275] As a result, as illustrated in FIG. 11, the anti-PD-L1×CD47 trivalent HCAb (PPC Nb-IgG4) has been confirmed to have an antitumor effect of up to about 74.4% compared to that of the negative control (Isotype group).
Claims 1, 4, 6 10, 15-17 and 23 encompass a broad genus of bispecific antibody that bispecifically binds to PD-L1 and CD47 nanobodies.
The USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018.
See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
In contrast to applicant’s reliance of describe the epitope of the PD-L1×CD47 in providing a fully characterized antigen / specific epitope as well as claiming structural elements of the antigen, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-PD-L1×CD47 NB to demonstrate possession.
Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding antibodies Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may bind. There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.
The anti-PD-L1×CD47 NB are required to practice the invention. The specification also fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely relying on the identification of PD-L1×CD47 as the antigen and the well-known structure of antibodies in general. However, the claims do not recite a general antibody, but an antibody having a specific desired activity. However, Federal Circuit clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
The claims are directed to a genus of anti-PD-L1×CD47 NB. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed anti-PD-L1×CD47 NB to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
For instance, citing to Centocor, the Court analogized an antigen and antibody to a lock and a key. For an antigen where there is only a finite number of binding antibodies, discovering those antibodies may be routine and conventional, and description of the antigen alone may be sufficient. By contrast, for antigens with millions of keys, or millions of potentially binding antibodies, description of the antigen and even a couple of examples may be far from sufficient.
Artisans are well aware that knowledge of a given antigen (for instance PD-L1 and CD47) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al (J Mol Biol. 2003 Nov 14;334(1): 103-18) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the FICDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al (Protein Eng Des Sel. 2009 Mar;22(3):159-68) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al (J Immunol. 2004 Dec 15; 173(12):7358-67) disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al (Nat Rev Immunol. 2019 Jun; 19(6):355-368) teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 x 1014).
Given the claimed broadly class of anti-PD-L1×CD47 NB and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed class of anti-PD-L1×CD47 NB, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims
AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163
Also, the specification at best describes plan for making nanobodies that bind PD-L1×CD47 NB and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient.
Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
"When a patent claims a genus using functional language to define a desired result, 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" (Capon v. Eshhar, 418 F.3d 1349 (fed. Cir. 2005)) (emphasis added).
"A sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
However, the anti-PD-L1 sdAb and the anti-CD47 sdAb are required to practice the invention. The specification also fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely rely on the identification of PD-L1 and CD47 as the antigen and the well-known structure of sdAb in general. However, the claims do not recite a general antibody, but an antibody having a specific desired activity.
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence, see MPEP 2163. Here, with respect to making anti-PD-L1 sdAb and anti-CD47 sdAb, the unpredictability is best demonstrated by the recent court decision in AbbVie v. Janssen Biotech and Centocor Biologics (Fed. Cir. 2014), the court found that AbbVie's generic claim can be classified as a set of human antibodies defined functionally by their high affinity and neutralizing activity to the human IL-12 antigen. However, AbbVie did not disclose any structural features common to the members of the genus. Rather, AbbVie's patent described only one type of structurally similar antibodies rather than antibodies representative of the full scope of the genus.
Absent any teaching of structure-function relationships, the skilled in the art cannot determine the critical amino acids in the CDR in the recited sequence and also possess the recited function. See AbbVie Deutschland GmbH v. Janssen Biotech, Inc. (Fed. Cir. 2014).
The facts of AbbVie parallel the claimed invention and provide significant guidance on the inherent unpredictability of protein engineering and the effect of amino acid substitutions on protein function. Abbvie is similar to the Federal Circuit's discussion in Novozymes A/S et al. v. Dupont Nutrition Biosciences APS et al., 2013 WL 3779376, Case No. 2012-1433, C.A.Fed; in both, the Federal Circuit emphasized the unpredictability in the art associated with changes in a parent enzyme or protein that can be effected at one or more positions in the sequence by amino acid addition, deletion, or substitution with at least nineteen other possibilities, e.g. counting natural amino acid residues. The basis of the unpredictability is rooted in the same principles that make improvements rare, namely that numerous subtle differences between amino acid residues determine protein binding and function. Because the subtle energetic contributions of each of these interactions is extraordinarily difficult to precisely quantify, and because the number of these interactions is so high even for a single protein-protein interface, innumerable small inaccuracies are amplified into unpredictability. This unpredictability is axiomatic in the field of protein engineering.
For example, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 ("[T]he 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."); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity. Moreover, the '128 and '485 patents of AbbVie do not describe any common structural features of the claimed antibodies. The asserted claims attempt to claim every fully human IL-12 antibody that would achieve a desired result, i.e., high binding affinity and neutralizing activity, and cover an antibody as different as Stelara, whereas the patents do not describe representative examples to support the full scope of the claims.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of anti-PD-L1 sdAb and anti-CD47 sdAb or variants falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406. Applicant has provided one anti-PD-L1 sdAb comprising the CDRs of SEQ ID NO: 2, 3, 4 and the anti-CD47 sdAb comprsing the CDRs of SQ ID NOs: 7, 8, 9, no other variants are discloses to have the claimed function of PD-L1XCD47 sdAbs. Recitation of specific amino acid substitutions in the CDRs are not representative of the genus. Thus, under Lilly and its progeny, their Specification would not have shown possession of a sufficient number of sequences failing within their potentially large genus to establish possession of their claimed genus. Cf. Enzo, 323 F.3d at 964, 63 USPQ2d at 1612 (“if the functional characteristic of … binding to [EphrinB2] were coupled with a disclosed correlation between that function and a structure that is sufficiently known or disclosed,” the written description requirement may be met).
With respect to the recitation an antibody which does not comprise all 3 CDRs of the sdAbs, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material ((https://www.aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “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.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
14. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
15. Claims 1, 12, 13, 14, are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Pat. 11840567 (of record).
The `567 patent teaches an antibody that binds CD47 and PD-L1, and is characterized in that a binding site to CD47 and PD-L1 is VHH mono-domains (see col., 25, lines 23+). The CDR of antigen-binding region or the whole antibody antigen binding region of the invention is derived from lama donor library with certain amino acid residues altered, e.g., substituted with different amino acid residues in order to optimize the properties of the specific antibodies (see col., 9, lines 25+, col., 12, lines 45+), preferably by conservative substitution (see col., 14,ines 12+).
The reference teachings anticipate the instant claims.
16. Claims 1, 12-17, 20 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 20220289848 A1.
The `848 publication provided an anti-CD47/anti-PD-L1 multiple antigen binding protein (e.g., a HCAb, i.e., “heavy-chain-only”) variant comprising a variant Fc region comprising one or more amino acid substitutions which increase half-life and/or improve binding to the neonatal Fc receptor (FcRn) [0206].
One or more amino acid modifications may be introduced into the Fc region of the anti-CD47/anti-PD-L1 multiple antigen binding protein or antigen binding fragment thereof provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions [0200].
The sdAb-Fc fusion proteins were constructed by linking sdAb to the N-terminus of human IgG4 Fc portion, with mutations S228P and L235E, called IgG4PE, generating new Fc fusion proteins called sdAb-PDL1a-IgG4PE, sdAb-PDL1b-IgG4PE and sdAb-PDL1c-IgG4PE [0307] .
The reference teachings anticipate the claimed in vnetion
17. Claims 1, 12-17, 20 and 23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by CN112745392B.
The `392 publication provides a bispecific antibody comprising (a) a PD-L1 single-domain antibody and (b) a CD47 single-domain antibody (see English abstract).
The `392 publication teaches a bispecific antibody, wherein said bispecific antibody comprises: two anti-PD-L1 single domain antibodies and two anti-CD 47 single domain antibodies, and the bispecific antibody has a structure from N-terminus to C-terminus represented by formula i (a):
P-L1-P-L2-Fc-L3-B-L4-B formula I (a), wherein,"-" is a peptide bond; L1, L2, L3, and L4 are each independently a peptide bond or a linker element; p is anti-PD-L1 single domain antibody, and the amino acid sequence is shown in SEQ ID NO. 1; b is an anti-CD 47 single domain antibody, the amino acid sequence of which is shown in SEQ ID NO 3, and fc is the Fc segment of the antibody (published claim 1), wherein the Fc domain is as shown in SEQ ID No. 6 at position 273-501, wherein L1, L3, and L4 are linker elements, and L2 is a peptide bond, wherein the amino acid sequence of the linker element is set forth in SEQ ID No. 2, wherein the amino acid sequence of the bispecific antibody is set forth in SEQ ID NO 6, bispecific fusion protein characterized in that said bispecific fusion protein is a dimer formed by two bispecific antibodies, wherein the bispecific fusion protein has a structure from N-terminus to C-terminus according to formula II:
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(see published claims). The `392 publication teaches that the Fc segment is an IgG4 type Fc segment
The `392 publication teaches an immunoconjugate is provided, the immunoconjugate contains:
(a) the bispecific antibody of the first aspect of the present invention, the bispecific fusion protein of the second aspect of the present invention; and
(b) a conjugation moiety selected from the group consisting of detectable labels, drugs, toxins, cytokines, radionuclides, or enzymes, gold nanoparticles/nanorods, nanomagnetic particles, viral coat proteins or VLPs, or their combination.
The `392 publication teaches a polypeptide fragment, derivative or analog of the present invention may be (i) a polypeptide having one or more conservative or non-conservative amino acid residues (preferably conservative amino acid residues) substituted, and such substituted amino acid residues may or may not be encoded by the genetic code, or (ii) a polypeptide having a substituent group in one or more amino acid residues, or (iii) a mature polypeptide with another compound
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The reference teachings anticipate the claimed invention.
18. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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19. Claims 1, 6, 8-10, 12-17, 19, 20, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18951146 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the `146 application are directed to a bispecific antibody that binds bispecifically to PD-L1 and CD47, comprising: a first humanized single domain antibody (first anti-PD-L1 hsdAb) or an antigen-binding fragment thereof, which specifically binds to PD-L1; and a second humanized single domain antibody (second anti-CD47 hsdAb) or an antigen-binding fragment thereof, which specifically binds to CD47, wherein the first anti-PD-L1 hsdAb or an antigen-binding fragment thereof comprises a CDRl-3 of SEQ ID NO: 2-4, wherein the second anti-CD47 hsdAb or an antigen-binding fragment thereof comprises a CDR1-3 of SEQ ID NO: 9-11, wherein the first anti-PD-L1 hsdAb or an antigen-binding fragment thereof, or the second anti-CD47 hsdAb mprises a VH of SEQ ID NO: 16, or the first anti-PD-L1 hsdAb or an antigen-binding fragment thereof, or the second hsdAb or an antigen-binding fragment thereof, comprises a heavy chain variable domain framework sequence having at least 85% sequence identity to the sequence of SEQ ID NO: 17, wherein the first hsdAb or an antigen-binding fragment thereof, or the second hsdAb or an antigen-binding fragment thereof, comprises a heavy chain variable domain framework sequence having 100% sequence identity to the sequence of SEQ ID NO: 16 or SEQ ID NO: 17.
Alignment of claimed SEQ ID NOs: 7-8-9 with referenced SEQ ID NO: 17
Qy 1 GLTFFRKYA-----------------IYSDRRI--------------------------- 16
||||||||| |||||||
Db 26 GLTFFRKYAVGWARQVPGKGLERVSRIYSDRRIEYLDAVKGRFTISRDNAKNTVYLQMNS 85
Qy 17 -----------ATGLRVGLTGWDEYDY 32
||||||||||||||||
Db 86 LKTEDTAVYYCATGLRVGLTGWDEYDY 112
Alignment of claimed SEQ ID NOs: 2-3-4 with referenced SEQ ID NO: 16
Qy 1 GFTFSSFA-----------------INTGGDST--------------------------- 16
|||||||| ||||||||
Db 26 GFTFSSFAMSWVRQAPGKGLEWVSDINTGGDSTDYADSVKGRFTISRDNAKNTLYLQMNS 85
Qy 17 -----------AKGPKEMVHVYSQ 29
|||||||||||||
Db 86 LKPEDTAVYYCAKGPKEMVHVYSQ 109
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
20. No claim is allowed.
21. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Baek et al. Abstract 2719: Papiliximab, a bispecific nanobody targetingCD47 and PDL1 retards tumor growth without hemolysis. Cancer Res (2024) 84 (6_Supplement): 2719.
Baek et al developed a bispecific single-domain antibody (nanobody, Nb) that targets both CD47 and PD-L1 with a minimal hemagglutination risk. Using phage display libraries from alpacas immunized withrecombinant antigens, we screened for an anti-CD47 Nb and an anti-PD-L1 Nb. The affinities (Kd)of these Nbs for their antigens were 7.0 × 10−9 and 9.7 × 10−9, respectively. To maximize affinity forboth antigens, a bispecific antibody (Papiliximab) was designed to tandemly array anti-CD47 andPD-L1 Nbs with the Fc region of IgG4. Papiliximab has a lower affinity for RBC (up to 3 μM) thanconventional anti-CD47 MoAbs reported earlier. Papiliximab successfully inhibited interactionsbetween CD47/SIRP-α and PD-L1/PD-1, with IC50 values of 7.09 nM and 2.67 nM, respectively.
22. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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August 4, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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