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`UK Intellectual Property Office
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`P066910GB:HRG/SJD/JPS
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`2nd March 2017
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`Dear Sirs,
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`Re: United Kingdom Patent Application No. 1519921.9
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`Shire ViroPharma Incorporated
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`Chartered Pate nt Atto rneys
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`European Patent Attorneys
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`Chartered Trade Mark Attorneys
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`Solicitors
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`Carpmaels &Ransford LLP
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`One Southampton Row
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`London WC'IB SHA
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`United Kingdom
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`T +44 20 7242 8692
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`F +44 20 7405 4166
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`email@carpmaels.com
`E
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`www.carpmaels.com
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`We write in reply to the examination report dated 1st December 2016. The enclosed description has
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`been updated to address the formalities requirements identified by the Examiner, and so the
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`application documents are now in line for grant.
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`A retrospective extension of two months to the deadline of 3rd January 2017 is hereby requested.
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`Overview
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`The third party observations do not impact the Examiner’s assessment ofthe claimed subject-
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`matter. The arguments in the observations either restate arguments already considered and deemed
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`overcome by the Examiner, or are new arguments based on aspirational interpretations of the cited
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`documents and riddled with hindsight. Bringing the due level of scrutiny to the documents reveals
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`that none undermines the Examiner’s conclusion that the claimed subject-matter is patentable.
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`Indeed, many documents actually agree with the applicant‘s prior arguments.
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`each LLP is open for inspection at the registered office. The word partner is intended to refer to a member of an LLP.
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`We also take the opportunity to address below the arguments in the anonymous third party
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`observations. Observations have also been filed against the EP patent application derived from the
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`same PCT as this application (EP 147623433). For the Examiner’s ease of reference, copies of the
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`documents cited by the observer (CSL) in the EPO proceedings but not provided by the observer on
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`this application are also enclosed. These documents are introduced and discussed below, where
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`appropriate in our submission, and forthe remaining documents in the final subsection of the
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`response.
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`office at One
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`Southampton Row, London, WC1 B SHA. Each entity is a separate limited liability partnership registered in England and
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`Wales. Carpmaels & Ransford LLP (Regd. No. OC882284) and Carpmaels & Ransford (Specialities) LLP (Regd. No.
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`0C4] 4i i S) are regulated by the Intellectual Property Regulation Board. Carpmaels & Ransford (International) LLP (Regd.
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`No. OC397628) is authorised and regulated by the Solicitors Regulation Authority (SRA ID 620864). A list of members of
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`CSL EXHIBIT 1068
`CSL v. Shire
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`Page 1 of 41
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`CAWMAELgéRANSl-TORD
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`Forthe Examiner’s ease of comparison, the comments below will track the arrangement of the third
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`party observations.
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`A. General disclosures relating to subcutaneous formulations
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`The anonymous observer criticises the applicant for relying on general statements made in D7 and
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`D8, when the applicant had said that the general statements in D6 should not be relied upon by the
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`Examiner. The observer then concludes with the assertion that “[/]t is not clear how the skilled
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`person would know which general statements are applicable and which are not”.
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`Curiously, the observer considers this conclusion to demonstrate the correctness of its position. On
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`the contrary, the observer’s conclusion supports precisely the point the applicant made in its
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`previous letter. The skilled person would not know ifthe general statement in D6 were or were not
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`specifically applicable to C1-INH. Consequently, there can be no ab initio expectation that a low
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`volume, high concentration formulation can be made for any given product.
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`B. No disclosure in the prior art of suitability of C1 -INH for subcutaneous administration at
`concentrations as recited in claim 1
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`References already on file
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`First, the anonymous observer discusses D1, D2, D5a and D5b. None ofthe observer’s comments is
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`As pointed out previously, D1 relates to administration of high volume, low concentration C1-INH. No
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`amount of window dressing in declaration B11 with regard to the disclosure of D1 changes this fact.
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`D1 teaches the skilled person nothing about the claimed subject-matter; it merely reinforces the
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`understanding of the field that a commercially viable high concentration, low volume formulation
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`according to the claims could not be achieved. The applicant cannot understand the observer’s
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`reference to D5b; this was published m the filing date. The reference to D5b “corroborating” what
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`was disclosed in D1, and therefore purportedly being indicative ofthe skilled person’s view, serves
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`only to highlight the misplaced hindsight in the observer’s arguments, in turn caused by a failure of
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`the observer’s declarant (and presumed employee) to look at the prior art objectively as ofthe
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`priority date1.
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`The observer’s arguments on D2 do not state anything new. As noted in the applicant’s previous
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`response (and discussed in more detail again below), D2 discloses high concentration solutions of
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`C1-INH, but it is purely an academic study and provides no indication ofthe possibility of the use of
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`C1-INH in a pharmaceutical, where stability and syringeability are important considerations.
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`Furthermore, this document was published decades before the priority date, and the observer
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`provides no explanation beyond bald assertion of why the teaching in this document, which is
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`1 Notably, the observer’s declarant is a trained veterinarian. His positions at CSL have been in pre-clinical and clinical testing.
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`He is not someone with hands-on experience of protein formulation and so his views on what would be achievable for any
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`given protein do not carry any weight.
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`Page 2 of41
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`Page 2 of 41
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`CAWMAELgéRANSl-TORD
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`purportedly so relevant to the claimed subject-matter, had not been acted upon before. Again,
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`hindsight prevails in the observer’s comments.
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`The arguments on D5a, which discloses the combination administration of high volume, low
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`concentration C1-INH with hyaluronidase, are similarly tainted. The observer cherry picks from the
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`entire disclosure that there is no explicit mention that C1-INH is unsuitable fortherapeutic use at
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`higher concentrations. This observation lacks common sense and commercial awareness — after all,
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`why, if making compositions as claimed were so simple and straightfonNard, would any investment
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`have been made in the entirely different strategy of combined administration with hyaluronidase?
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`D5a’s unidirectional teaching is that C1-INH is not suitable for subcutaneous administration at high
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`concentrations. The comments ofthe investigator in charge ofthe trial (the same as the author on
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`B1/B2 cited by the observer) could not be more clear in this regard:
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`"our goal is to optimize the delivery and convenience of self-administration of Cinryze,
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`and we believe that the combination with rHuPH20 offers us the best opportunity to
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`achieve that goal. The initiation of this important phase 2 study is an essential step
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`toward continually enhancing the Cinryze experience for all patients who seek greater
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`control over their disease through routine prevention."
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`The prior art already on file establishes that at the priority date, the understanding in the field was
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`that C1-INH is not suitable for subcutaneous administration at high concentrations, and that another
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`strategy was required to deliver C1-INH subcutaneously.
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`The observer’s irrelevant new citations
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`B4 and B10 are new documents, but their relevance to the proceedings relies on a favourable
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`interpretation ofa number of points. Insofar as the portions to which the observer refers, none is a
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`worked example. Everything is a paper disclosure, and paper disclosures of various generic features
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`that the observer can assert is borderline relevant only if interpreted in a particular way. Put simply,
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`neither document is any more relevant than the general comments in D6 discussing SC
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`administration, balanced against the comments that SC formulation is unique protein-to-protein;
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`neither document teaches the claimed subject-matter or provides explicit motivation for the skilled
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`person to generate the claimed subject-matter.
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`For B4, first, both the selection ofthe minimum value forthe volume and the maximum value forthe
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`dose in a paper disclosure on page 18, lines 5-7, must be chosen even to get a value nearto the
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`400U/ml mentioned for subcutaneous injection in claim 1. Next, the observer presents calculations
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`with the conclusion that B4 teaches almost 400U/ml compositions. Of course, the observer neglects
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`to say that taking the opposite end of each scale (i.e. highest volume and lowest dose) results in
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`0.4U/ml doses. The reasonable interpretation ofthis document, as would be taken by the skilled
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`person, is that the lower doses apply to the lower volumes, and the higher doses to the higher
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`volumes — the range in paper disclosure B4 is more in the order of tens to a hundred U/ml; in line
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`with the standard formulations of ~50U/ml at the time B4 was written. It is also noteworthy that B4
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`was published 12 years before the priority date, but no explanation is provided by the observer as to
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`why this document was not acted upon by the skilled person during this time if its disclosure is
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`indeed so relevant. The observer’s argument also tries to make something ofthe fact that the dose
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`is disclosed for intramuscular injection, and equates this to subcutaneous injection. However, the
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`Page 3 of41
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`Page 3 of 41
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`CAWMAELgéRANSl-TORD
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`injected tissues in IM and SC administration have markedly different structures and so in any case
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`the therapeutic contexts are not directly comparable. Accordingly, references relating to IM
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`administration would not be consulted by the skilled person in looking to generate C1-lNH
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`compositions for SC C1-lNH administration. B4 would not be identified or consulted by the skilled
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`person, and in any case, B4’s disclosure still falls far short of relevant.
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`B10 is a paper disclosure in which C1-lNH is mentioned in a dependent claim. Such a disclosure,
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`when the examples ofthe cited document do not relate to C1-lNH, cannot be evidence that there is
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`no issue with formulating specific proteins that are not tested in that document. And certainly not any
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`one specific untested protein from the series of untested proteins in the laundry list of proteins set
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`out in the claims of B10. As set out by reference to D7 and D8 in the applicant’s previous response,
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`formulation of biopharmaceuticals is highly protein specific. It is not possible, a priori, to make any
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`conclusions vis-a-vis formulation for SC administration without experimental data demonstrating the
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`suitability ofthe formulation forthis purpose.
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`Summam
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`The observer makes no argument that has not already been considered and rejected by the
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`Examiner in reaching the conclusion that the pending claims are allowable. D1, D2 and D5a provide
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`no motivation forthe skilled person to make high concentration C1-lNH compositions for SC use.
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`The observer’s reliance on D5b is inappropriate because D5b is a post-filing publication, but in any
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`case D5b is nonetheless a publication on high volume, low concentration SC administration of
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`C1-lNH. Together with the strong teaching in D5a that “combination with rHuPH20 offers us the M
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`opportunity” to achieve SC administration of C1-lNH, there is no question that the skilled person at
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`the priority date did not consider C1-lNH to be suitable for subcutaneous administration at
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`concentrations as recited in the claims. The observer’s irrelevant paper disclosures of formulations in
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`B4 and B10 have no impact on this conclusion.
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`C. No motivation in the prior art to use a composition as recited in claim 1
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`The applicant never disputed the general desire noted in D6 (and B11) to make small volume doses
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`for SC administration. But again, the observer misses the point. lnventive step is based on the facts
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`ofthe case, and the relevant facts here are that the claimed subject-matter was never made nor
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`suggested, and the line of development in SC administration of C1-INH pointed towards high
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`volume, low concentration administration, which could only be deemed to indicate difficulties with
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`low volume, high concentration formulations. The general desire for low volume, high concentration
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`formulations for SC administration does not trump the specific appreciation ofthe facts surrounding
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`C1-lNH set out in our last letter, as supported by D7 and D8 which make clearthat in the field of
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`protein formulation for SC administration it is necessary to consider each protein on a case-by-case
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`basis; such is the nature of biological products. Thus the motivation to make SC C1-lNH according
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`to the claims must be based on the documents in the field ofC1-lNH preparations; it cannot come
`from documents like D6.
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`We set out in our previous response that this perspective is encapsulated in the judgment in Conor
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`Medsystems Inc vAngiotech Pharmaceuticals Inc [2008] UKHL 49; [2008] R.P.C. 28, where Lord
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`Hoffmann approved the remarks of Kitchin J. in Generics (UK) Ltd v H Lundbeck A/S [2007] EWHC
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`1040 ((Pat); [2007] R.P.C. 32, which said:
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`Page 4 of41
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`Page 4 of 41
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`CAWMAELgéRANSl-TORD
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`“The question of obviousness must be considered on the facts of each case.”
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`New Documents B1 and BZ
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`The main thrust ofthe observations is based on these two related documents, and the crucial part of
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`the disclosure is said to be Figure 1 of BZ. This figure is said by the observerto disclose the
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`administration of C1-lNH at 333U/ml, and this is as far as the observer wants to considerthe
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`documents. The observer presents the now familiar line that “there is no specific mention that there
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`was any problem with this formula”.
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`Again, as set out previously, the absence of a specific criticism of a particular method or feature
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`does not at all mean that it is recommended by the art. Indeed, the foremost fatal flaw ofthis
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`argument from the observer is that it ignores what it simply plain from the documents, considering
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`the whole contents of B1 and BZ as the skilled person would do, ratherthan focussing on only the
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`allegedly-relevant disclosure in Figure 1. If everything were as straightfonNard, and as routine, to
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`generate a 400U/ml composition as the observer portrays, it would make no sense forthe authors of
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`BZ to abandon such a simple and straightfon/vard approach (even continuing to administerthe
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`333U/ml calculated by the observer without raising the concentration), and instead set out
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`development of an entirely different strategy. This different strategy was to combine SC C1-lNH with
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`something called in Figure 1 of BZ “rHuPH20”, which is the HalozymeT'VI hyaluronidase discussed in
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`our previous response with reference to D5a (to recap, this enzyme “acts by removing traditional
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`limitations on the volume of drugs that can be delivered subcutaneous/V. Hyaluronidase therefore
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`permits larger volume, and so lower concentration, SC administration ofdrugs).
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`This combination was then administered in a single injection of 1000U in 10 ml or 2000U in 20ml (at
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`100U/ml). So even if we were to follow the observer’s argument that 333U/ml was administered in
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`the Prior 200 study, the observer does not explain why nine months later, in full knowledge of the
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`results of the earlier trial, the authors of BZ abandoned the allegedly obvious path of continuing
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`with a low volume, high concentration monoformulation and instead proceeded to investigate a lower
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`concentration co-formulation with hyaluronidase. Notably, the observer cannot point to anything in
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`other documents that affects the recommendation in BZ to carry fon/vard the high volume, low
`concentration co-formulation.
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`Thus, at the priority date, development in the field of SC administration ofC1-lNH was towards high
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`volume, low concentration formulations, and so away from the SC administration of a low volume,
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`high concentration C1-lNH composition as recited in claim 1. The claimed subject-matter is therefore
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`inventive, because as ofthe priority date, the skilled person would not have been motivated to make
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`compositions as recited in claim 1 for subcutaneous use.
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`Documents published between BZ and the priority date
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`In the EPO observations, the observer cited a further document which is considered relevant, but
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`which has not yet been considered by the examiner on this application (enclosed herewith as D9). At
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`the EPO, the observer clearly appreciated the glaring flaw in BZ as set out in the above paragraphs
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`(abandonment of low volume, high concentration C1-lNH formulations in favour of high volume, low
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`concentration formulations), and tried to address this shortfall by reference to D9. D9 is a press
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`Page 5 of41
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`Page 5 of 41
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`CAWMAELgéRANSl-TORD
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`release from August 2012, which notes that the FDA put a temporary hold on a Phase II trial testing
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`the combination of C1-lNH with hyaluronidase. Based on this document, the EPO observer said
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`“these studies were stopped [. . .],' such that the skilled person would thus, at the filing date, not have
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`considered the option of administering volumes above 2m] in combination with hyaluronidase”.
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`This assertion is incorrect. As shown by D5a, by December 2012 (just a few months before the
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`priority date), the FDA’s temporary hold had been lifted. The Phase llb trial on the combination had
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`been “initiated’ (i.e. the first patients had already been dosed). As noted above, the comments ofthe
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`investigator in charge ofthe trial (the same as the author on BZ) in D5a set out that "our goal is to
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`optimize the delivery and convenience of self-administration of Cinryze, and we believe that the
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`combination with rHuPH20 offers us the best opportunity to achieve that goal. The initiation of this
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`important phase 2 study is an essential step toward continually enhancing the Cinryze experience
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`for all patients who seek greater control over their disease through routine prevention."
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`For completeness, the observer’s reference to documents such as B13 is also not of relevance. This
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`is a document from CSL which mentions its intention to develop a “volume-reduced” form oftheir
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`C1-lNH product BerinertT'V'. However, no indication is provided as to what is meant by “volume-
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`reduced”. After all, in CSL’s D1/D5b studies on SC administration, it administered 20ml of a 50U/ml
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`formulation, which therefore provides a variety of scopes for reduced volumes — for instance the
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`volume-reduced form could be one which upped the concentration to 100U/ml, thereby reducing the
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`volume by half (which would then replicate a formulation used in the BZ poster). In any case, B13 is
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`silent regarding the teaching ofthe generation of compositions of 400U/ml as recited in claim 1 for
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`subcutaneous use, and so cannot provide any relevant motivation to the skilled person with regard
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`to this subject-matter. Moreover, the teaching in B13 must be considered in context in the field,
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`which as set out above contains the explicit rejection in the BZ poster of low volume, high
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`concentration formulations of C1-lNH (but still outside of the claims) in favour ofthe HalozymeT'VI
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`hyaluronidase co-formulation, and further supported by the contents of D5a.
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`Thus, at the priority date, the focus in the field is confirmed to have been on the development ofa
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`combination product ofC1-INH and hyaluronidase. This combination allowed the SC delivery of high
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`volume doses of C1-lNH, which enabled those doses to be of low C1-lNH concentration. This focus
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`on high volume, low concentration, combination products was reached despite even the
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`administration of SC C1-lNH which the observer calculated to be at 333U/ml. At best, the 333U/ml
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`might be deemed to be a “high water mark" in terms of the concentration in C1-lNH administered
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`before the priority date, which the art reiected and retreated from to focus on high volume, low
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`concentration formulations as ofthe priority date at which the invention must be assessed.
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`Summary
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`In our last letter, we concluded as follows:
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`“D5[a], D4 and D1 all relate to real world examples of the SC administration of C1 -
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`INH. D4 and D1 administer C1-INH SC simply by taking the IV formulation and
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`administering the same volume SC as would be provided IV. There would be no
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`reason to do so if, as the Examiner contends, it was oven/vhelmingly straightfon/vard
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`to formulate C1 -INH in a small volume for SC use. From these documents alone, the
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`skilled person would understand that it was plainly not simple to reformulate C1 -INH
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`Page 6 of41
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`Page 6 of 41
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`CAWMAELgéRANSI-TORD
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`from IV to SC compositions. This understanding is furthermore strongly reinforced by
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`D5 (published between D1/D4 and the priority date) which, as quoted above, sets
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`out a combination administration of C1-INH with a product whose purpose is to
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`permit greater volumes of active to be administered (i.e. to make easier the
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`administration of high volume, low concentration SC doses of C1 -INH).”
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`B1 and B2 as provided by the observer directly support this analysis. B1 and B2 report that even
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`having reached a concentration ~80% of the level in claim 1, the art still returned to the use of high
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`volume, low concentration formulations.
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`The teaching of documents on file which actually relate to the SC administration of C1-INH is away
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`from high concentration, low volume formulation according to claim 1. The teaching in the relevant
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`prior art instead focusses on facilitating the administration of higher volume, lower concentration
`doses.
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`The question still remains outstanding: if, as the observer alleges, all that was required to
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`make compositions as recited in claim 1 was effectively to concentrate prior art
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`compositions, why had it not been done before?
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`The applicant posed this question to the Examiner in our letter prior to the Examiner’s indication that
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`the claims on file were allowable. The anonymous observer does not answer the question in its
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`observations. Forthe Examiner’s ease of reference, the relevant portion of our letter is set out again
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`below, adapted to discuss the observer’s position:
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`C1-INH has been administered IV to treat hereditary angioedema (HAE) since the 1980s. If SC
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`administration simply required the concentration and optimisation of prior formulations as purported
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`by the Examiner, then surely this step would have been taken overthe last three decades. As noted
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`in Schlumberger Holdings Ltd v Electromagnetic Geoservices AS [2010] EWCA Civ 819:
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`“If a useful development was, in hindsight, seemingly obvious for years and the
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`apparently straightforward technical step from the prior art simply was not taken, then
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`there is likely to have been an invention.”
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`Thus, unexplained delay points toward invention. In Virgin Atlantic Airways v Premium Aircraft
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`Interiors UK [2010] R.P.C. 8 [2009] EWCA Civ 1062, a delay ofjust six years was seen to be
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`relevant in indicating an inventive step. In Convatec v Smith & Nephew [2011] EWHC 2039 (Pat), a
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`ten-year delay without any product emerging on the market was considered to indicate
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`inventiveness. The delay in the present case is a multiple of the delays considered to imply an
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`invention in these judgments.
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`Furthermore, in Convatec v Smith & Nephew, the court made comments that are particularly
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`relevant to the present case. The court held that it was necessary to look at what actually happened
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`in the field; the skilled person is not divorced from reality. In the present case the observer ignores
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`this guidance from the courts. Instead, the observer overlooks the contemporaneous art within the
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`C1-INH field which focusses on administration of high volume, low concentration C1-INH
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`compositions, optionally with co-formulation. Following the observations, the Examiner can now see
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`that the teaching in the art (B2) is that even following testing ofa C1-INH composition of alleged
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`Page 7 0f41
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`Page 7 of 41
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`CAWMAELgéRANSl-TORD
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`concentration 333U/ml, still the field moved towards lower concentration formulations using
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`HalozymeT'VI hyaluronidase. B2 was published in March 2012 and in the timeline ofthe development
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`ofthe field was followed by D5a, a press release from December 2012 — i.e. made following and with
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`knowledge of the B2 trial. D5a is the disclosure ofthe commencement of the Phase llb clinical trial
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`using the HalozymeT'VI hyaluronidase drug delivery platform to accommodate lower concentration
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`formulations, which was the strategy pursued in the absence of any teaching to make high
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`concentration, low volume doses of C1-lNH for SC administration according to the claims in the
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`preceding decades and even in light ofthe B2 report that C1-lNH had been administered at what the
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`The applicant notes in particularthat the observer now suggests that there would be no hurdle to
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`making high concentra