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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Election/Restrictions
Applicant’s election without traverse of:
PF4
Injection
Intravenous injection
Age-related cognitive decline
50 years or older
Neurodegenerative disease
Alzheimer’s disease
Working memory
Motor function
in the reply filed on 4/22/26 is acknowledged. The Examiner confirms that an election for Eii or Eiii was not required (see “if” in original restriction mailed 6/17/25).
Claims 1-25 are pending. Claim 7 is withdrawn as being drawn to a non-elected species (election C). Claim 10 is withdrawn as being drawn to a non-elected species (election D). Claims 13-18 are withdrawn as being drawn to a non-elected species (election E). These claims are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/22/26.
Claims 1-6, 8-9, 11-12, and 19-25 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p.44. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Sequences meeting the requirement for a SEQ ID must be accompanied by said SEQ ID. For example, page 4 recites KKIIKK at line 9, which is at least four enumerated amino acids and so requires a SEQ ID.
Drawings
The drawings are objected to because:
Figure 1B contains a legend where -3 and +3 are represented by the same grey color. This makes the shading in the figure uninterpretable.
Figure 1C contains a “40” on the x-axis that is cut off.
Figure 6 has been submitted upside down.
Figure 6A contains a legend where min and max are represented by the same grey color. This makes the shading in the figure uninterpretable.
Figure 7B: the text labeling the columns overlaps itself making the text illegible.
Figure 12: the washout is a dashed line, which appears three times. The three different concentrations of PF4 are all given the same solid grey line, making it unclear if the three solid lines in the graph are individually all three concentrations or if each line represents one of the concentrations.
Figure 14B: the text is small to the point of being illegible.
Figure 14D: there appears to be text on the graph, but the text is small and light in color to the point of being illegible.
Figure 14F: the labels in the graph are too small to be legible.
Figure 15A/D/G: whatever text is above “2-3h LTP recording” is not legible, being too small/light/blurry.
Figure 16A: there appears to be text on the cross at day 2, the Y on and near day 20, and possibly in the box on day 3, but the details are not legible/interpretable.
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.
Claim Objections
Claims 1 and 25 are objected to because of the following informalities:
MPEP §2173.05(s) notes that incorporation by reference to a specific figure or table is permitted only in exceptional circumstances. In this case, there appears to be no compelling reason the contents of the table or figure could not be reproduced in the claim itself.
Further, the instant specification defines “systemic” and “peripheral” as synonyms (paragraph 23). Inclusion of both terms in the claim could suggest that there is some difference when there is in fact none. One of the two terms should be removed as a duplicate. There is also the potential for confusion when “the administering” in, e.g., claim 4 at first appears to be indefinite, referring to either “the systemic administering” or “the peripheral administering” in claim 1 despite these being an identical administration step.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-6, 8-9, 11-12, and 19-25 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.
Reference to a table in a claim is generally a formality issue; see claim objection above. However, in this case, the reference also introduces indefiniteness over the scope of the claim. Claims 1 and 25 require administering a protein comprising “a polypeptide of table 1 or table 2”. However, it is unclear what information in this table is being used as a limitation and what is not.
For example, on its face, it would appear that a “polypeptide of table 1” is not simply PF4, but PF4 with the specific SEQ ID listed in the table at the specific ratio of Kl/Veh. This ratio is never described by the specification and the term itself is indefinite as it is unclear what “Kl/Veh” is meant to describe or how the ratio relates to the claimed administration step.
Further, this interpretation is undermined by claims such as claim 3, which does not require the sequence attributed to PF4 in table 1. This raises the question of what “a polypeptide of table 1” is limited to if not the descriptors in the referenced table. While claim 3 is limited to a certain sequence, it is unclear if the other columns in the table are meant to provide limitations as suggested by the claim or if they are not as suggested by dependent claim 3.
The indefiniteness is compounded by the fact that PF4 appears in both table 1 and table 2, but with different sequences. This further suggests that the additional columns are meant to provide claim limitations when referencing the table, but if this were the case then claim 3 would violate §112d for being broader than the sequence set forth in the table.
Therefore, claims 1-6, 8-9, 11-12, and 19-25 are indefinite.
Claims 1-6, 8-9, 11-12, and 19-25 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.
The claims are directed to proteins or “functional fragment or variant thereof”. The limits of a “functional fragment” are indefinite. The function of the protein is critical as without any function, the protein would not achieve the claimed goal of improving cognition. However, there is more than one function of, e.g., PF4 and it is unclear what sequences are required of the claimed “functional fragment” or which function must be preserved. For example, the specification states that the heparin binding site of PF4 (a functional domain) may or may not be present (paragraph 21). This suggests that a peptide consisting of KKIIKK—which is a functional fragment of PF4 that binds heparin—is not within the claim scope because the alternative of this domain being absent means that this domain is not responsible for the cognitive improvement. This makes it unclear what functional fragments of PF4 or the other claimed proteins are within the scope of the claim because there is more than one “function” of these proteins, while clearly not all functional fragments will result in the claimed outcome. This is similar to the “effective amount” in MPEP §2173.05(c) where the claim was indefinite without stating the function and more than one effect is disclosed in the specification.
Therefore, claims 1-6, 8-9, 11-12, and 19-25 are indefinite.
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 1-6, 8-9, 11-12, and 19-25 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 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.
The claims are directed to a method of improving e.g., cognition by administering a protein or a functional fragment or variant thereof. However, these functional fragments and variants fail to meet the written description requirement.
One means of providing adequate written description and evidence of possession of a claimed genus is through providing sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the fragments and variants must improve cognitive function as per the claim. However, claim 1 does not require any particular sequence for these fragments/variants. For example, the specification states that PF4 operates by “moderating the effects of heparin-like molecules” (paragraph 22) but that the heparin binding site of PF4 (a functional domain) may or may not be present (paragraph 21). So, while this KKIIKK sequence is a functional fragment, clearly this is not descriptive of the function that improves cognition as it may be absent. Paragraph 21 also states that PF4 may have zero helices and “fewer than nine of the beta strands”, i.e., potentially zero beta strands. There is no particular structure of PF4 nor any of the other claimed proteins responsible for the cognitive improvement and as such the skilled artisan could not envisage which fragments are the required “functional fragments” effective for the claimed result. In the same way, without description of the amino acids required for the claimed function, the skilled artisan could not envisage the variant structures that preserve that function.
In a second way, the specification might provide a representative number of species for the claimed genus that would convey to the artisan possession of the whole genus. However, in this case, the species disclosed to not represent the full breadth of all possible members of the genus. For PF4, the specification discloses the human sequences (SEQ ID NOs: 1 and 2) and labels two mouse versions by Uniprot ID. The description of human and mouse sequences does not allow the skilled artisan to envisage the sequences in other species (Fiddes v. Baird, 30 USPQ2d 1481 at 1483). Further, the specification does not disclose any particular functional fragments which are responsible for the claimed function.
With respect to variants, the specification discloses 3 potential PF4 variants at paragraph 22: P58L, K66E, and L67H. Paragraph 22 also references Kuo 2013, but this document was not provided nor cited on an IDS and so has not been considered. Paragraph 70 states that homologs and allelic variants from any species are usable in the claimed method, but this is not a description of the proteins and the skilled artisan could not envisage the particular sequence of the protein from this description. Variants in paragraph 70 are stated to include “at least one” conserved or non-conserved amino acid mutation and so “variants” as used by the specification includes changing up to every single amino acid in the protein where the only description of valid changes are the three in paragraph 22.
In a narrower claim, claim 3 encompasses proteins 90% identical to SEQ ID NO: 1. However, for the same reasons as above, this does not provide adequate guidance to the skilled artisan as to which amino acids are relevant to the required function and so one could not envisage the particular sequences for the claimed fragments or variants that would improve cognitive function in a subject. SEQ ID NO: 1 is 70 amino acids long, allowing for altering 7 arbitrary amino acids into any of the other 19 amino acids (or any synthetic or amino acid analog; paragraph 28) where the only guidance is that 1) the KKIIKK sequence is not required and 2) residues 58, 66, and 67 may be mutated to L, E, and H, respectively.
The above rationale applies to the other proteins as well as for improving motor function.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of 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). As discussed above, the artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides, fragments, and variants, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF' s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, claims 1-6, 8-9, 11-12, and 19-25 do not meet the written description requirement.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-4, 6, 11-12, and 25 is/are rejected under 35 U.S.C. 102(a)(1-2) as being anticipated by Yang (US20110262393; form 892) as evidenced by Andrade (form 892).
Regarding claim 1, Yang teaches a method of treating a neural disease by administering PF4 (claim 19), wherein the neural disease is Alzheimer’s (AD)(claim 21). A subject with Alzheimer’s disease meets the limitation of an individual in need of improved cognitive function (see instant claim 12). See also Yang paragraph 67 noting that Alzheimer’s disease is preceded by “mild” cognitive impairment (paragraph 67), clearly indicating that this impairment gets worse as the disease develops. While it is appreciated that PF4 is listed as an alternative to other therapeutics in claim 19, MPEP §2131.02(II) sets forth that “a reference that clearly names the claimed species anticipates the claim no matter how many other species are named”. Thus, Yang teaches administering PF4 (a polypeptide found in both Table 1 and Table 2) to a subject in need of improving cognitive function.
With respect to systemic administration, Yang teaches formulating pharmaceutical compositions as parenteral injection (paragraph 70).
With respect to “improving cognitive function”, Yang teaches the method is one of treating Alzheimer’s disease (above), which is characterized by diminished cognitive function and so an improvement would be expected when treating this disease; note that the instant specification includes “reduced decline” within the scope of improved cognition (paragraph 25). Further, MPEP § 2112 (II), which states, "there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003)." A reference teaching a process may anticipate claims drawn to a method comprising the same process steps, despite the recitation of a different intended use in the preamble or the later discovery of a particular property of one of the starting materials or end products (Integra Life Sciences I Ltd. v. Merck KGaA, 50 USPQ2d 1846 (DC SCalif, 1999)). The court has noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003). See MPEP § 2111.04). As Yang is administering the same drug (PF4) to the same population (a subject in need of improved cognitive function), the same result will occur.
Regarding claim 2, Yang teaches administering PF4 as above.
Regarding claim 3, Yang teaches the PF4 has a sequence of SEQ ID NO:2 (paragraph 49), which comprises an amino acid sequence 100% identical to instant SEQ ID NO: 1.
Regarding clam 4, Yang teaches administration by injection as above.
Regarding claim 6, Yang teaches the subject is human (paragraphs 75, 82, 98, and 108).
Regarding claims 11 and 12, Yang teaches treating Alzheimer’s disease as above.
Regarding claim 25, the instant specification is evidence that a subject having a neurodegenerative disease is a subject in need of improved motor function (paragraph 88). Alzheimer’s disease is a neurodegenerative disease and so the method of Yang, which administers the same drug to treat the same disease, must also achieve the same results. Further, in light of the specification, the person “in need” of improved motor function is everyone in the same way that those in need of improved cognition includes everyone (paragraph 26, which discloses those in need are anyone who desires the improvement). Finally, as evidenced by Andrade, motor function decline is a symptom of Alzheimer’s disease and so those with AD are in need of improved motor function.
Therefore, claims 1-4, 6, 11-12, and 25 are anticipated by Yang.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4, 6, 11-12, 19-21 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang (US20110262393) evidenced by Andrade.
Claims 1-4, 6, 11-12, and 25 are anticipated as above and therefore obvious for the same reasons.
Regarding claim 19, Yang does not explicitly teach administering PF4 at the claimed range. However, Yang teaches administration is a result effective variable, selected on the basis of a number of factors such as route of administration, body weight, and age (paragraph 72). Yang teaches that 25ng/mL of PF4 is protective against Aß induced neuronal death (figure 10; paragraph 179). Yang teaches administering MSCs or the proteins contained in MSCs (paragraph 69), which includes PF4 and teaches administering the MSCs based on body weight (paragraph 72).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP §2144.05(II).
“[I]t is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions” (MPEP §2144.05(II)(A)).
In this case, at the time of filing, it would have been obvious to administer PF4 based on the body weight of the patient because Yang teaches body weight is a variable to consider for dosing and explicitly teaches administering other therapeutics per kg of body weight. Yang teaches at least one amount that was reduced to practice and is demonstrably neuroprotective. This coupled with Yang’s teachings to consider result effective variables when formulating a dose would have motivated the person of ordinary skill in the art to discover workable doses through routine optimization. There is no objective evidence to suggest the critical nature of Applicant’s claimed range and so there would have been a reasonable expectation of success when optimizing one known effective dose into another based on the articulated variables of Yang. Discovery of a particular concentration (dose) would therefore have been obvious.
Regarding claim 20, Yang teaches administering MSCs or the proteins contained in MSCs (paragraph 69), which includes PF4. Yang teaches administering the MSCs in multiple doses (paragraph 72). This same paragraph teaches administration “per day”, suggesting a minimum of two days of treatment and that treatment is every day. While Yang does not explicitly suggest administering PF4 more than once, one of ordinary skill in the art would have found it obvious to do so because Yang teaches administering other therapeutics more than once. Further, Yang teaches Alzheimer’s is an “aging-related chronic inflammatory disease” (paragraph 50). Given that AD is a chronic disease, one of ordinary skill in the art would have found it obvious to provide more than a single dose of the treatment.
Regarding claim 21, Yang teaches administering MSCs or the proteins contained in MSCs (paragraph 69), which includes PF4. Yang teaches administering the MSCs in multiple doses (paragraph 72). This same paragraph teaches administration “per day”, suggesting a minimum of two days of treatment and that treatment is every day. While Yang does not explicitly teach PF-4 administered once every day, it would have been obvious to do so because Yang teaches other therapeutics formulated in a “per day” dose form.
Therefore claims 1-4, 6, 11-12, 19-21 and 25 would have been obvious.
Claim(s) 8-9 and 22-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang (US20110262393) evidenced by Andrade as applied to claims 1-4, 6, 11-12, 19-21 and 25 above, and further in view of Smith (US20180169048; form 892).
The discussion of claims 1-4, 6, 11-12, 19-21 and 25 are above and incorporated herein.
Yang teaches Alzheimer’s disease “destroys memory” (paragraph 3) and is associated with memory loss (paragraph 65). Yang is silent regarding testing the individual before and after administration for working memory.
Regarding claim 22, it would have been obvious to a person of ordinary skill in the art to test the cognitive function of an individual being treated for Alzheimer’s disease after administering said treatment. Yang teaches memory deficits are a symptom of Alzheimer’s disease and that PF4 is neuroprotective. Smith is also concerned with treating Alzheimer’s disease in a human subject (claim 51). Smith uses the “Telephone Interview for Cognitive Status” (TICS) to measure cognition at 24 months after treatment (figure 3; paragraph 239), demonstrating the effectiveness of the treatment.
It would have been obvious to use the method of Smith to evaluate/monitor treatment efficacy in the method of Yang, thereby arriving at the limitations of claim 22. All of the limitations were known in the prior art, the only difference being their actual combination. However, one could have combined these elements to obtain predictable results where each merely performs the same function as they do separately. In this case, the method of Yang serves as a means of treating a subject with AD while the testing of Smith serves to monitor the efficacy of that treatment. There would have been a reasonable expectation that improvement on the TICS test would indicate cognitive improvement irrespective of the treatment being administered.
See MPEP 2141(II)(C): "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
In this case, it would have been obvious to monitor the treatment of Yang using the test of Smith because Yang teaches the treatment for treating AD and Smith teaches the test will evaluate improvements in cognition in those with AD as a result of treatment.
Regarding claim 23, Smith also teaches a measurement at T=0 (figure 3) and the establishment of a “baseline” (paragraph 228). It would have been obvious to the person of ordinary skill in the art to similarly establish a baseline cognitive test prior to treatment when monitoring the method of Yang because Smith teaches doing so. Moreover, by establishing a pre-treatment level, it would have been obvious that this level could be compared to post-treatment levels to evaluate therapeutic efficacy of the Yang treatment in the predictable manner that Smith uses such a comparison, e.g., figure 3.
Regarding claim 24, Smith teaches using a variety of tests known in the art to evaluate cognitive function (paragraph 177). This includes evaluating working memory and tests such as CANTAB (paragraph 177). It would have been obvious to use a known method of evaluating Alzheimer’s disease because, as above, it would have been obvious to monitor the effect of treatment by way of monitoring cognitive decline/improvements and it would have been predictable to use a test known for evaluating this in an Alzheimer’s patient, including the evaluation of working memory.
Regarding claim 8, Yang teaches Alzheimer’s is an “aging-related chronic inflammatory disease” (paragraph 50), thereby teaching incidence of AD increases with age. Smith corroborates this, teachings administering the AD treatment to subjects at least 50 years of age (paragraphs 73, 179, and 180; claim 51). The art of record does not provide any evidence nor reasoning to suggest that the method of Yang or the testing of Smith would not predictably function based on a patient’s age. As such, it would have been obvious to include subjects age 50+ when treating AD using the method of Yang.
Regarding claim 9, the instant specification does not have a special definition for “age related cognitive decline”. Yang teaches Alzheimer’s is an “aging-related chronic inflammatory disease” (paragraph 50) and the art teaches AD is associated with cognitive decline (Yang paragraph 67; Smith clam 51). The cognitive decline of AD is part of an age-related disease and therefore a subject with AD meets the broadest reasonable interpretation of a subject with an age relate cognitive decline.
Therefore, claims 1-4, 6, 8-9, 11-12, and 19-25 would have been obvious.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yang (US20110262393) evidenced by Andrade as applied to claims 1-4, 6, 11-12, 19-21 and 25 above, and further in view of Guo (form 892).
The discussion of claims 1-4, 6, 11-12, 19-21 and 25 are above and incorporated herein.
Yang teaches systemic injection of PF-4 as discussed above. Yang does not teach a specific systemic administration point for the injection.
One of ordinary skill in the art at the time of filing, having been instructed to administer PF-4 via systemic injection, would have found it obvious to use known routes for said injection. Guo teaches PF-4 is suitable for intravenous administration (figure 1; paragraph 1535 C1), rendering this route of administration obvious.
Therefore, claims 1-6, 11-12, 19-21 and 25 would have been obvious.
Conclusion
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/Adam Weidner/ Primary Examiner, Art Unit 1675
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